Clinical Review

Real progress was achieved in 2018 in the effort to reduce the US maternal mortality rate, the highest of any developed nation and where women of color are 3 to 4 times more likely than others to die of childbirth-related causes. Importantly, the United States is the only nation other than Afghanistan and Sudan where the rate is rising.¹

In May 2019, the Centers for Disease Control and Prevention (CDC) published a Vital Signs document focused on preventable maternal deaths.² It affirmed that about 60% of the 700 pregnancy-related deaths that occur annually in the United States are preventable, and it provided important information on when and why these deaths occur.

Among the CDC findings, about:

• one-third of deaths (31%) occurred during pregnancy (before delivery)
• one-third (36%) occurred at delivery or in the week after
• one-third (33%) occurred 1 week to 1 year postpartum.

In addition, the CDC highlighted that:

• Heart disease and stroke caused more than 1 in 3 deaths (34%). Infections and severe bleeding were other leading causes of death.
• Black and American Indian/Alaska Native women were about 3 times as likely to die from a pregnancy-related cause as white women.

The American College of Obstetricians and Gynecologists (ACOG), under the leadership of President Lisa Hollier, MD, MPH (2018–2019), fully embraced the challenge and responsibility of meaningfully improving health care for every mom. In this article, I review some of the critical steps taken in 2018 and preview ACOG’s continued commitment for 2019 and beyond.

Efforts succeed: Bills are now laws of the land

ACOG and our partner organizations, including the Society for Maternal-Fetal Medicine and the March of Dimes, have long recognized the value of state-based maternal mortality review committees (MMRCs) in slowing and reversing the rate of maternal mortality. An MMRC brings together local experts to examine the causes of maternal deaths—not to find fault, but to find ways to prevent future deaths. With the right framework and support, MMRCs already are providing us with data and driving policy recommendations.

Supporting MMRCs in all states. With this in mind, ACOG helped pass and push to enactment HR 1318, the Preventing Maternal Deaths Act of 2018 (Public Law No. 115-344), a bipartisan bill designed to help develop and provide support for MMRCs in every state. The bill was introduced in the US House of Representatives by Rep. Jaime Herrera Beutler (R-WA) and Rep. Diana DeGette (D-CO) and in the US Senate by Sen. Heidi Heitkamp (D-ND) and Sen. Shelley Moore Capito (R-WV). ACOG Fellow and US Rep. Michael Burgess, MD (R-TX), also was instrumental in the bill’s success. The CDC is actively working toward implementation of this law, and grantees are expected to be announced by the end of September.

Continue to: In addition, ACOG worked with Congress...

In addition, ACOG worked with Congress to secure $50 million in federal funding to reduce maternal mortality, allocated thusly:

• $12 million to support state MMRCs
• $3 million to support the Alliance for Innovation on Maternal Health
• $23 million for State Maternal Health Innovation Program grants
• $12 million to address maternal mortality in the Healthy Start program.

As these federal congressional initiatives worked their way into law, the states actively supported MMRCs as well. As of this writing, only 3 states—North Dakota, South Dakota, and Wyoming—have not yet developed an MMRC.³

Filling the gaps in ObGyn care. Another key ACOG-sponsored bill signed into law will help bring more ObGyns into shortage areas. Sponsored by Rep. Burgess, Rep. Anna Eshoo (D-CA), and Rep. Lucille Roybal-Allard (D-CA) and by Sen. Tammy Baldwin (D-WI) and Sen. Lisa Murkowski (R-AK), the Improving Access to Maternity Care Act (Public Law No. 115-320) requires the Department of Health and Human Services to identify maternity health professional target areas for use by the National Health Service Corps to bring ObGyns to where they are most needed.

Following up on that new law, ACOG currently is working closely with the American Academy of Family Physicians (AAFP) and the National Rural Health Association (NRHA) on the unique challenges women in rural areas face in accessing maternity and other women’s health care services. In June, Dr. Hollier represented ACOG at the Rural Maternal Health forum, which was convened by the Centers for Medicare and Medicaid and sponsored by ACOG, AAFP, and NRHA.⁴ We are pursuing policies designed to increase the number of ObGyns and other physicians who choose to train in rural areas and increase the clinical use of telehealth to help connect rural physicians and patients with subspecialists in urban areas.

Projects in the works

Congress is ready to do more. Already, 5 ACOG-supported bills have been introduced, including bills that extend women’s Medicaid coverage to 12 months postpartum (consistent with coverage for babies), support state perinatal quality collaboratives, and more. This interest is augmented by the work of the recently formed congressional Black Maternal Health Caucus, focused on reducing racial disparities in health care. In July, ACOG joined 12 members of Congress in a caucus summit to partner with these important congressional allies.

ACOG is expanding support for these legislative efforts through our work with another important ally, the American Medical Association (AMA). ACOG’s delegation to the 2019 Annual Meeting of the AMA House of Delegates in June scored important policy wins, including AMA support for Medicaid coverage for women 12 months postpartum and improving access to care in rural communities.

There is momentum on Capitol Hill to take action on these important issues, and ACOG’s priority is to ensure that any legislative package complements the important work many ObGyns are already doing to improve maternal health outcomes. ACOG has an important seat at the table and will continue to advocate each and every day for your practices and your patients as Congress deliberates legislative action.

Continue to: Your voice matters...

Your voice matters

Encourage your representatives in the House and the Senate to support ACOG-endorsed legislation and be sure they know the importance of ensuring access to women’s health care in your community. Get involved in advocacy; start by visiting the ACOG advocacy web page (www.acog.org/advocacy). Also note that members of Congress are back in their home states during seasonal breaks and many hold town halls and constituent meetings. The health of moms and babies is always an important issue, and you are the expert.

ACOG’s commitment to ensuring healthy moms and babies, and ensuring that our members can continue providing high-quality care, runs through everything we do.

Acknowledgments

The author thanks ACOG former Vice President for Health Policy Barbara Levy, MD, ACOG Senior Director Jeanne Mahoney, and ACOG Federal Affairs Director Rachel Tetlow for their helpful review and comments.

Real progress was achieved in 2018 in the effort to reduce the US maternal mortality rate, the highest of any developed nation and where women of color are 3 to 4 times more likely than others to die of childbirth-related causes. Importantly, the United States is the only nation other than Afghanistan and Sudan where the rate is rising.¹

In May 2019, the Centers for Disease Control and Prevention (CDC) published a Vital Signs document focused on preventable maternal deaths.² It affirmed that about 60% of the 700 pregnancy-related deaths that occur annually in the United States are preventable, and it provided important information on when and why these deaths occur.

Among the CDC findings, about:

• one-third of deaths (31%) occurred during pregnancy (before delivery)
• one-third (36%) occurred at delivery or in the week after
• one-third (33%) occurred 1 week to 1 year postpartum.

In addition, the CDC highlighted that:

• Heart disease and stroke caused more than 1 in 3 deaths (34%). Infections and severe bleeding were other leading causes of death.
• Black and American Indian/Alaska Native women were about 3 times as likely to die from a pregnancy-related cause as white women.

The American College of Obstetricians and Gynecologists (ACOG), under the leadership of President Lisa Hollier, MD, MPH (2018–2019), fully embraced the challenge and responsibility of meaningfully improving health care for every mom. In this article, I review some of the critical steps taken in 2018 and preview ACOG’s continued commitment for 2019 and beyond.

Efforts succeed: Bills are now laws of the land

ACOG and our partner organizations, including the Society for Maternal-Fetal Medicine and the March of Dimes, have long recognized the value of state-based maternal mortality review committees (MMRCs) in slowing and reversing the rate of maternal mortality. An MMRC brings together local experts to examine the causes of maternal deaths—not to find fault, but to find ways to prevent future deaths. With the right framework and support, MMRCs already are providing us with data and driving policy recommendations.

Supporting MMRCs in all states. With this in mind, ACOG helped pass and push to enactment HR 1318, the Preventing Maternal Deaths Act of 2018 (Public Law No. 115-344), a bipartisan bill designed to help develop and provide support for MMRCs in every state. The bill was introduced in the US House of Representatives by Rep. Jaime Herrera Beutler (R-WA) and Rep. Diana DeGette (D-CO) and in the US Senate by Sen. Heidi Heitkamp (D-ND) and Sen. Shelley Moore Capito (R-WV). ACOG Fellow and US Rep. Michael Burgess, MD (R-TX), also was instrumental in the bill’s success. The CDC is actively working toward implementation of this law, and grantees are expected to be announced by the end of September.

Continue to: In addition, ACOG worked with Congress...

In addition, ACOG worked with Congress to secure $50 million in federal funding to reduce maternal mortality, allocated thusly:

• $12 million to support state MMRCs
• $3 million to support the Alliance for Innovation on Maternal Health
• $23 million for State Maternal Health Innovation Program grants
• $12 million to address maternal mortality in the Healthy Start program.

As these federal congressional initiatives worked their way into law, the states actively supported MMRCs as well. As of this writing, only 3 states—North Dakota, South Dakota, and Wyoming—have not yet developed an MMRC.³

Filling the gaps in ObGyn care. Another key ACOG-sponsored bill signed into law will help bring more ObGyns into shortage areas. Sponsored by Rep. Burgess, Rep. Anna Eshoo (D-CA), and Rep. Lucille Roybal-Allard (D-CA) and by Sen. Tammy Baldwin (D-WI) and Sen. Lisa Murkowski (R-AK), the Improving Access to Maternity Care Act (Public Law No. 115-320) requires the Department of Health and Human Services to identify maternity health professional target areas for use by the National Health Service Corps to bring ObGyns to where they are most needed.

Following up on that new law, ACOG currently is working closely with the American Academy of Family Physicians (AAFP) and the National Rural Health Association (NRHA) on the unique challenges women in rural areas face in accessing maternity and other women’s health care services. In June, Dr. Hollier represented ACOG at the Rural Maternal Health forum, which was convened by the Centers for Medicare and Medicaid and sponsored by ACOG, AAFP, and NRHA.⁴ We are pursuing policies designed to increase the number of ObGyns and other physicians who choose to train in rural areas and increase the clinical use of telehealth to help connect rural physicians and patients with subspecialists in urban areas.

Projects in the works

Congress is ready to do more. Already, 5 ACOG-supported bills have been introduced, including bills that extend women’s Medicaid coverage to 12 months postpartum (consistent with coverage for babies), support state perinatal quality collaboratives, and more. This interest is augmented by the work of the recently formed congressional Black Maternal Health Caucus, focused on reducing racial disparities in health care. In July, ACOG joined 12 members of Congress in a caucus summit to partner with these important congressional allies.

ACOG is expanding support for these legislative efforts through our work with another important ally, the American Medical Association (AMA). ACOG’s delegation to the 2019 Annual Meeting of the AMA House of Delegates in June scored important policy wins, including AMA support for Medicaid coverage for women 12 months postpartum and improving access to care in rural communities.

There is momentum on Capitol Hill to take action on these important issues, and ACOG’s priority is to ensure that any legislative package complements the important work many ObGyns are already doing to improve maternal health outcomes. ACOG has an important seat at the table and will continue to advocate each and every day for your practices and your patients as Congress deliberates legislative action.

Continue to: Your voice matters...

Your voice matters

Encourage your representatives in the House and the Senate to support ACOG-endorsed legislation and be sure they know the importance of ensuring access to women’s health care in your community. Get involved in advocacy; start by visiting the ACOG advocacy web page (www.acog.org/advocacy). Also note that members of Congress are back in their home states during seasonal breaks and many hold town halls and constituent meetings. The health of moms and babies is always an important issue, and you are the expert.

ACOG’s commitment to ensuring healthy moms and babies, and ensuring that our members can continue providing high-quality care, runs through everything we do.

Acknowledgments

The author thanks ACOG former Vice President for Health Policy Barbara Levy, MD, ACOG Senior Director Jeanne Mahoney, and ACOG Federal Affairs Director Rachel Tetlow for their helpful review and comments.

Real progress was achieved in 2018 in the effort to reduce the US maternal mortality rate, the highest of any developed nation and where women of color are 3 to 4 times more likely than others to die of childbirth-related causes. Importantly, the United States is the only nation other than Afghanistan and Sudan where the rate is rising.¹

In May 2019, the Centers for Disease Control and Prevention (CDC) published a Vital Signs document focused on preventable maternal deaths.² It affirmed that about 60% of the 700 pregnancy-related deaths that occur annually in the United States are preventable, and it provided important information on when and why these deaths occur.

Among the CDC findings, about:

• one-third of deaths (31%) occurred during pregnancy (before delivery)
• one-third (36%) occurred at delivery or in the week after
• one-third (33%) occurred 1 week to 1 year postpartum.

In addition, the CDC highlighted that:

• Heart disease and stroke caused more than 1 in 3 deaths (34%). Infections and severe bleeding were other leading causes of death.
• Black and American Indian/Alaska Native women were about 3 times as likely to die from a pregnancy-related cause as white women.

The American College of Obstetricians and Gynecologists (ACOG), under the leadership of President Lisa Hollier, MD, MPH (2018–2019), fully embraced the challenge and responsibility of meaningfully improving health care for every mom. In this article, I review some of the critical steps taken in 2018 and preview ACOG’s continued commitment for 2019 and beyond.

Efforts succeed: Bills are now laws of the land

ACOG and our partner organizations, including the Society for Maternal-Fetal Medicine and the March of Dimes, have long recognized the value of state-based maternal mortality review committees (MMRCs) in slowing and reversing the rate of maternal mortality. An MMRC brings together local experts to examine the causes of maternal deaths—not to find fault, but to find ways to prevent future deaths. With the right framework and support, MMRCs already are providing us with data and driving policy recommendations.

Supporting MMRCs in all states. With this in mind, ACOG helped pass and push to enactment HR 1318, the Preventing Maternal Deaths Act of 2018 (Public Law No. 115-344), a bipartisan bill designed to help develop and provide support for MMRCs in every state. The bill was introduced in the US House of Representatives by Rep. Jaime Herrera Beutler (R-WA) and Rep. Diana DeGette (D-CO) and in the US Senate by Sen. Heidi Heitkamp (D-ND) and Sen. Shelley Moore Capito (R-WV). ACOG Fellow and US Rep. Michael Burgess, MD (R-TX), also was instrumental in the bill’s success. The CDC is actively working toward implementation of this law, and grantees are expected to be announced by the end of September.

Continue to: In addition, ACOG worked with Congress...

In addition, ACOG worked with Congress to secure $50 million in federal funding to reduce maternal mortality, allocated thusly:

• $12 million to support state MMRCs
• $3 million to support the Alliance for Innovation on Maternal Health
• $23 million for State Maternal Health Innovation Program grants
• $12 million to address maternal mortality in the Healthy Start program.

As these federal congressional initiatives worked their way into law, the states actively supported MMRCs as well. As of this writing, only 3 states—North Dakota, South Dakota, and Wyoming—have not yet developed an MMRC.³

Filling the gaps in ObGyn care. Another key ACOG-sponsored bill signed into law will help bring more ObGyns into shortage areas. Sponsored by Rep. Burgess, Rep. Anna Eshoo (D-CA), and Rep. Lucille Roybal-Allard (D-CA) and by Sen. Tammy Baldwin (D-WI) and Sen. Lisa Murkowski (R-AK), the Improving Access to Maternity Care Act (Public Law No. 115-320) requires the Department of Health and Human Services to identify maternity health professional target areas for use by the National Health Service Corps to bring ObGyns to where they are most needed.

Following up on that new law, ACOG currently is working closely with the American Academy of Family Physicians (AAFP) and the National Rural Health Association (NRHA) on the unique challenges women in rural areas face in accessing maternity and other women’s health care services. In June, Dr. Hollier represented ACOG at the Rural Maternal Health forum, which was convened by the Centers for Medicare and Medicaid and sponsored by ACOG, AAFP, and NRHA.⁴ We are pursuing policies designed to increase the number of ObGyns and other physicians who choose to train in rural areas and increase the clinical use of telehealth to help connect rural physicians and patients with subspecialists in urban areas.

Projects in the works

Congress is ready to do more. Already, 5 ACOG-supported bills have been introduced, including bills that extend women’s Medicaid coverage to 12 months postpartum (consistent with coverage for babies), support state perinatal quality collaboratives, and more. This interest is augmented by the work of the recently formed congressional Black Maternal Health Caucus, focused on reducing racial disparities in health care. In July, ACOG joined 12 members of Congress in a caucus summit to partner with these important congressional allies.

ACOG is expanding support for these legislative efforts through our work with another important ally, the American Medical Association (AMA). ACOG’s delegation to the 2019 Annual Meeting of the AMA House of Delegates in June scored important policy wins, including AMA support for Medicaid coverage for women 12 months postpartum and improving access to care in rural communities.

There is momentum on Capitol Hill to take action on these important issues, and ACOG’s priority is to ensure that any legislative package complements the important work many ObGyns are already doing to improve maternal health outcomes. ACOG has an important seat at the table and will continue to advocate each and every day for your practices and your patients as Congress deliberates legislative action.

Continue to: Your voice matters...

Your voice matters

Encourage your representatives in the House and the Senate to support ACOG-endorsed legislation and be sure they know the importance of ensuring access to women’s health care in your community. Get involved in advocacy; start by visiting the ACOG advocacy web page (www.acog.org/advocacy). Also note that members of Congress are back in their home states during seasonal breaks and many hold town halls and constituent meetings. The health of moms and babies is always an important issue, and you are the expert.

ACOG’s commitment to ensuring healthy moms and babies, and ensuring that our members can continue providing high-quality care, runs through everything we do.

Acknowledgments

The author thanks ACOG former Vice President for Health Policy Barbara Levy, MD, ACOG Senior Director Jeanne Mahoney, and ACOG Federal Affairs Director Rachel Tetlow for their helpful review and comments.

Atopic dermatitis (AD) is a chronic inflammatory skin condition with a lifetime prevalence of 15% to 20% in industrialized countries.¹ It affects both children and adults and is predominantly characterized by a waxing and waning course of eczematous skin lesions and pruritus. In recent years, there is increasing recognition that AD can present with extracutaneous findings. Large-scale epidemiologic studies have reported a notably higher prevalence of ophthalmic complications in the AD population compared to the general population, in a severity-dependent manner.^2,3 Potential complications include blepharitis, keratoconjunctivitis, keratoconus, glaucoma, cataracts, retinal detachment, ophthalmic herpes simplex virus infections, and dupilumab-associated ocular complications.

The etiology of each ocular complication in the context of AD is complex and likely multifactorial. Intrinsic immune dysregulation, physical trauma from eye rubbing, AD medication side effects, and genetics all have been speculated to play a role.² Some of these ocular complications have a chronic course, while others present with sudden onset of symptoms; many of them can result in visual impairment if undiagnosed or left untreated. This article reviews several of the most common ocular comorbidities associated with AD. We discuss the clinical presentation, pathophysiology, and management strategies for each condition.

Blepharitis

Blepharitis, an inflammatory condition of the eyelids, is estimated to affect more than 6% of patients with AD compared to less than 1% of the general population.² Blepharitis can be classified as anterior or posterior, based on the anatomic location of the affected region relative to the lash margin. Affected individuals may experience pruritus and irritation of the eyelids, tearing, a foreign body or burning sensation, crusting of the eyelids, and photophobia.⁴ Anterior blepharitis commonly is due to staphylococcal disease, and posterior blepharitis is secondary to structural changes and obstruction of meibomian gland orifices.

Although the pathophysiology is not well defined, xerosis in atopic patients is accompanied by barrier disruption and transepidermal water loss, which promote eyelid skin inflammation.

The mainstay of therapy for atopic blepharitis consists of conventional lid hygiene regimens, such as warm compresses and gentle scrubbing of the lid margins to remove crust and debris, which can be done with nonprescription cleansers, pads, and baby shampoos. Acute exacerbations may require topical antibiotics (ie, erythromycin or bacitracin applied to the lid margins once daily), topical calcineurin inhibitors (ie, cyclosporine ophthalmic emulsion 0.05%), or low-potency topical corticosteroids (ie, fluorometholone 0.1% or loteprednol etabonate 0.5% ophthalmic suspensions).⁵ Due to potential side effects of medications, especially topical corticosteroids, patients should be referred to ophthalmologists for definitive diagnosis and treatment.

Keratoconjunctivitis

Atopic keratoconjunctivitis (AKC) is a noninfectious inflammatory condition of the cornea and conjunctiva that occurs in an estimated 25% to 42% of patients with AD.^6,7 It frequently presents in late adolescence and has a peak incidence between 30 and 50 years of age.⁸ The symptoms of AKC include ocular pruritus, redness, ropy mucoid discharge, burning discomfort, photophobia, and blurring of vision. Corneal involvement can progress to corneal neovascularization and punctate or macroepithelial erosions and ulcerations, which increase the risk for corneal scarring and visual impairment.⁷

Keratoconjunctivitis is a complex inflammatory disease characterized by infiltration of the conjunctival epithelium by eosinophils, mast cells, and lymphocytes. On examination, patients frequently are found to have concurrent AD of the periorbital skin as well as papillary hypertrophy of the tarsal conjunctiva with accompanying fibrosis, which can lead to entropion (turning inward of the lid margins and lashes) in severe cases.⁷ Ophthalmic evaluation is strongly recommended for patients with AKC to control symptoms, to limit exacerbations, and to prevent sight-threatening inflammation leading to vision loss. Treatment can be challenging given the chronicity of the condition and may require multiple treatment arms. Conservative measures include cool compresses and treatment with ophthalmic eye drops containing antihistamines (ie, ketotifen 0.025% [available over-the-counter]) and mast cell stabilizers (ie, olopatadine ophthalmic solution 0.1%).⁸ Atopic keratoconjunctivitis exacerbations may require short-term use of topical steroids or calcineurin inhibitors, or systemic equivalents for refractory cases.⁶ Long-term maintenance therapy typically consists of proper eye hygiene and steroid-sparing agents that reduce ocular inflammation, such as topical cyclosporine and tacrolimus, neither of which are associated with increased intraocular pressure (IOP)(Figure 1).⁸ Cornea disease resulting from chronic conjunctival/lid microtrauma can be managed with soft or scleral contact lenses.

Keratoconus

Keratoconus is a noninflammatory ocular disorder characterized by progressive thinning and conelike protrusion of the cornea. The corneal topographic changes result in high irregular astigmatism and reduced visual acuity, which can manifest as image blurring or distortion (Figure 2).^2,9 Multiple case series and controlled studies have reported a positive association between keratoconus and a history of atopic disease.^10,11

The precise etiology of keratoconus in the context of AD is unclear and likely is multifactorial. Habitual eye rubbing from periocular pruritus and discomfort has been reported to be a notable contributor to keratoconus.¹² In addition, intrinsic inflammation and imbalance of cytokines and proteases also may contribute to development of keratoconus.¹³

Keratoconus is a progressive condition that can severely impact vision, making it critical to diagnose patients before irreversible vision loss occurs. Individuals with risk factors, such as AD of the eyelids, history of eye rubbing, or family history of keratoconus, should be advised to receive routine vision screening for worsening astigmatism, especially during the first few decades of life when keratoconus progresses rapidly.

The conservative management for early keratoconus includes glasses and gas-permeable contact lenses for correction of visual acuity and astigmatism. For advanced keratoconus, scleral lenses often are prescribed. These large-diameter, gas-permeable lenses are designed to rest on the sclera and arch over the entire cornea.⁹ Alternatively, corneal collagen cross-linking is a newer technique that utilizes riboflavin and UVA irradiation to strengthen the corneal tissue. It has proven to be safe and effective in slowing or stopping the progression of keratoconus, particularly when treated at the early stage, and received US Food and Drug Administration approval in 2016.⁹

Glaucoma

Glaucoma is a well-known complication of AD and can lead to irreversible ocular hypertension and optic nerve damage. Corticosteroid use is a major risk factor for glaucoma, and the rise in IOP is thought to be due to increased aqueous outflow resistance.¹⁴

Multiple case reports have linked glaucoma to long-term use of potent topical corticosteroids in the facial and palpebral regions, which has been attributed to direct steroid contact and absorption by ocular tissues, as glaucoma rarely occurs with topical steroid application elsewhere on the body.^15-17 Systemic steroids (ie, prednisolone) taken for more than 8 weeks also have been associated with a marked rise in IOP.¹⁸

Certain risk factors may predispose a steroid user to increased IOP, including existing open-angle glaucoma, diabetes mellitus, collagen disease, and high myopia.^15,19 Steroid responders and younger individuals also demonstrate increased sensitivity to steroids.²⁰

Given that glaucoma often is asymptomatic until advanced stages, early detection is the key for proper intervention. Periodic glaucoma screening by an ophthalmologist would be appropriate for known steroid responders, as well as patients with a prolonged history of topical steroid application in the palpebral region and systemic steroid use, family history of glaucoma, or known ocular pathology.²¹ Furthermore, patients with concurrent glaucoma and AD should be jointly managed by dermatology and ophthalmology, and systemic and topical corticosteroid use should be minimized in favor of alterative agents such as calcineurin inhibitors.²²

In addition to steroid-induced glaucoma, intrinsic atopic glaucoma recently has been proposed as a clinical entity and is characterized by increased inflammatory cytokines—IL-8 and CCL2—in the aqueous humor and abnormal accumulation of fibers in corneoscleral meshwork.²³

Cataracts

Cataracts are estimated to affect 8% to 25% of patients with AD.^21,24 Unlike age-related cataracts, cataracts associated with AD are observed in adolescents and young adults in addition to the older population. The progression of lenticular opacity can rapidly occur and has been reported to coincide with AD flares.^25,26

Patients with AD typically present with anterior or posterior subcapsular cataracts instead of nuclear and cortical cataracts, which are more common in the general population.^27,28 Anterior subcapsular cataracts are more specific to AD, whereas posterior subcapsular cataracts are associated with both prolonged corticosteroid use and AD.²⁶ Children generally are more sensitive to steroids than adults and may develop cataracts more rapidly and at lower concentrations.²⁹

The pathophysiology of cataract formation and progression in the context of AD is multifactorial. Cataract patients with AD have compromised blood-retinal barrier integrity as well as increased oxidative damage in the lens.^30,31 Genetics and blunt trauma from eye rubbing are thought to play a role, and the latter has been associated with faster progression of cataracts.²⁸ In contrast, corticosteroid-induced cataracts likely are caused by transcriptional changes and disrupted osmotic balance in the lens fibers, which can lead to fiber rupture and lens opacification.^26,32 Systemic corticosteroids show the strongest association with cataract development, but inhaled and topical steroids also have been implicated.²⁶

Although cataracts can be surgically corrected, prevention is critical. Patients with early-onset periorbital AD, prolonged use of topical or systemic corticosteroids, and family history of cataracts should be routinely screened. Anterior and posterior subcapsular cataracts are diagnosed with red reflex examinations that can be readily performed by the primary care physician or ophthalmologist.³³ Atopic dermatitis patients with cataracts should be advised to use calcineurin inhibitors and alternative treatments in place of corticosteroids.

Retinal Detachment

Retinal detachment (RD) is a serious complication of AD that can present in individuals younger than 35 years. The incidence of RD in patients with AD has been estimated to be 4% to 8%.³⁴ Retinal detachment manifests with visual disturbances such as flashing lights, shadows, visual field defect, and blurring of vision, but also may occur in the absence of vision changes.^35,36

Across multiple case series, patients who developed RD were consistently found to have AD in the facial or periorbital region and a history of chronic eye rubbing. Multiple patients also presented with concurrent proliferative vitreoretinopathy, lens subluxation, and/or cataracts.^35,37 The mechanism for RD has been attributed to ocular contusion from vigorous eye rubbing, as fundus findings between traumatic and AD-associated RD are similarly characterized by tractional breaks in the retina at vitreous base borders.³⁷

Avoidance of eye rubbing and optimized treatment of facial AD may help prevent RD in patients with AD. Furthermore, all patients with symptoms of RD should be immediately referred to ophthalmology for surgical repair.

Herpetic Ocular Disease

Ocular herpes simplex virus infections cause ocular pain and are associated with notable visual morbidity, as recurrences can result in irreversible corneal scarring and neovascularization. Two retrospective case-control studies independently reported that individuals with a history of AD are at greater risk for herpetic ocular disease compared to age-matched controls.^38,39 Furthermore, atopic disease is associated with higher recurrence rates and slower regeneration of the corneal epithelium.⁴⁰

These findings suggest that AD patients with a history of recurrent herpetic ocular diseases should be closely monitored and treated with antiviral prophylaxis and/or topical corticosteroids, depending on the type of keratitis (epithelial or stromal).⁴⁰ Furthermore, active ocular herpetic infections warrant urgent referral to an ophthalmologist.

Dupilumab-Associated Ocular Complications

Dupilumab, a monoclonal antibody that blocks IL-4 and IL-13 signaling, is the first biologic therapy to be approved for treatment of moderate to severe AD. Prior clinical trials have described a higher incidence of anterior conjunctivitis in dupilumab-treated AD patients (5%–28%) compared to placebo (2%–11%).⁴¹ Of note, the incidence may be as high as 70%, as reported in a recent case series.⁴² Interestingly, independent trials assessing dupilumab treatment in asthma, nasal polyposis, and eosinophilic esophagitis patients did not observe a higher incidence of conjunctivitis in dupilumab-treated patients compared to placebo, suggesting an AD-specific mechanism.⁴³

Prominent features of dupilumab-associated conjunctivitis include hyperemia of the conjunctiva and limbus, in addition to ocular symptoms such as tearing, burning, and bilateral decrease in visual acuity. Marked reduction of conjunctival goblet cells has been reported.⁴⁴ In addition to conjunctivitis, blepharitis also has been reported during dupilumab treatment.⁴⁵

Standardized treatment guidelines for dupilumab-associated ocular complications have not yet been established. Surprisingly, antihistamine eye drops appear to be inefficacious in the treatment of dupilumab-associated conjunctivitis.⁴¹ However, the condition has been successfully managed with topical steroids (fluorometholone ophthalmic suspension 0.1%) and tacrolimus ointment 0.03%.⁴¹ Lifitegrast, an anti-inflammatory agent approved for chronic dry eye, also has been suggested as a treatment option for patients refractory to topical steroids.⁴⁵ Alternatively, cessation of dupilumab could be considered in AD patients who experience severe ocular complications. Atopic dermatitis patients taking dupilumab who have any concerning signs for ocular complications should be referred to an ophthalmologist for further diagnosis and management.

Conclusion

Practicing dermatologists likely will encounter patients with concurrent AD and ocular complications. Although eye examinations are not routinely performed in the care of AD patients, dermatologists can proactively inquire about ocular symptoms and monitor patients longitudinally. Early diagnosis and treatment of these ocular conditions can prevent vision loss in these patients. Furthermore, symptomatic control of AD and careful consideration of the side-effect profiles of medications can potentially reduce the incidence of ocular complications in individuals with AD.

Patients with visual concerns or risk factors, such as a history of vigorous eye rubbing or chronic corticosteroid use, should be jointly managed with an ophthalmologist for optimized care. Moreover, acute exacerbations of ocular symptoms and visual deterioration warrant urgent referral to ophthalmology.

Atopic dermatitis (AD) is a chronic inflammatory skin condition with a lifetime prevalence of 15% to 20% in industrialized countries.¹ It affects both children and adults and is predominantly characterized by a waxing and waning course of eczematous skin lesions and pruritus. In recent years, there is increasing recognition that AD can present with extracutaneous findings. Large-scale epidemiologic studies have reported a notably higher prevalence of ophthalmic complications in the AD population compared to the general population, in a severity-dependent manner.^2,3 Potential complications include blepharitis, keratoconjunctivitis, keratoconus, glaucoma, cataracts, retinal detachment, ophthalmic herpes simplex virus infections, and dupilumab-associated ocular complications.

The etiology of each ocular complication in the context of AD is complex and likely multifactorial. Intrinsic immune dysregulation, physical trauma from eye rubbing, AD medication side effects, and genetics all have been speculated to play a role.² Some of these ocular complications have a chronic course, while others present with sudden onset of symptoms; many of them can result in visual impairment if undiagnosed or left untreated. This article reviews several of the most common ocular comorbidities associated with AD. We discuss the clinical presentation, pathophysiology, and management strategies for each condition.

Blepharitis

Blepharitis, an inflammatory condition of the eyelids, is estimated to affect more than 6% of patients with AD compared to less than 1% of the general population.² Blepharitis can be classified as anterior or posterior, based on the anatomic location of the affected region relative to the lash margin. Affected individuals may experience pruritus and irritation of the eyelids, tearing, a foreign body or burning sensation, crusting of the eyelids, and photophobia.⁴ Anterior blepharitis commonly is due to staphylococcal disease, and posterior blepharitis is secondary to structural changes and obstruction of meibomian gland orifices.

Although the pathophysiology is not well defined, xerosis in atopic patients is accompanied by barrier disruption and transepidermal water loss, which promote eyelid skin inflammation.

The mainstay of therapy for atopic blepharitis consists of conventional lid hygiene regimens, such as warm compresses and gentle scrubbing of the lid margins to remove crust and debris, which can be done with nonprescription cleansers, pads, and baby shampoos. Acute exacerbations may require topical antibiotics (ie, erythromycin or bacitracin applied to the lid margins once daily), topical calcineurin inhibitors (ie, cyclosporine ophthalmic emulsion 0.05%), or low-potency topical corticosteroids (ie, fluorometholone 0.1% or loteprednol etabonate 0.5% ophthalmic suspensions).⁵ Due to potential side effects of medications, especially topical corticosteroids, patients should be referred to ophthalmologists for definitive diagnosis and treatment.

Keratoconjunctivitis

Atopic keratoconjunctivitis (AKC) is a noninfectious inflammatory condition of the cornea and conjunctiva that occurs in an estimated 25% to 42% of patients with AD.^6,7 It frequently presents in late adolescence and has a peak incidence between 30 and 50 years of age.⁸ The symptoms of AKC include ocular pruritus, redness, ropy mucoid discharge, burning discomfort, photophobia, and blurring of vision. Corneal involvement can progress to corneal neovascularization and punctate or macroepithelial erosions and ulcerations, which increase the risk for corneal scarring and visual impairment.⁷

Keratoconjunctivitis is a complex inflammatory disease characterized by infiltration of the conjunctival epithelium by eosinophils, mast cells, and lymphocytes. On examination, patients frequently are found to have concurrent AD of the periorbital skin as well as papillary hypertrophy of the tarsal conjunctiva with accompanying fibrosis, which can lead to entropion (turning inward of the lid margins and lashes) in severe cases.⁷ Ophthalmic evaluation is strongly recommended for patients with AKC to control symptoms, to limit exacerbations, and to prevent sight-threatening inflammation leading to vision loss. Treatment can be challenging given the chronicity of the condition and may require multiple treatment arms. Conservative measures include cool compresses and treatment with ophthalmic eye drops containing antihistamines (ie, ketotifen 0.025% [available over-the-counter]) and mast cell stabilizers (ie, olopatadine ophthalmic solution 0.1%).⁸ Atopic keratoconjunctivitis exacerbations may require short-term use of topical steroids or calcineurin inhibitors, or systemic equivalents for refractory cases.⁶ Long-term maintenance therapy typically consists of proper eye hygiene and steroid-sparing agents that reduce ocular inflammation, such as topical cyclosporine and tacrolimus, neither of which are associated with increased intraocular pressure (IOP)(Figure 1).⁸ Cornea disease resulting from chronic conjunctival/lid microtrauma can be managed with soft or scleral contact lenses.

Keratoconus

Keratoconus is a noninflammatory ocular disorder characterized by progressive thinning and conelike protrusion of the cornea. The corneal topographic changes result in high irregular astigmatism and reduced visual acuity, which can manifest as image blurring or distortion (Figure 2).^2,9 Multiple case series and controlled studies have reported a positive association between keratoconus and a history of atopic disease.^10,11

The precise etiology of keratoconus in the context of AD is unclear and likely is multifactorial. Habitual eye rubbing from periocular pruritus and discomfort has been reported to be a notable contributor to keratoconus.¹² In addition, intrinsic inflammation and imbalance of cytokines and proteases also may contribute to development of keratoconus.¹³

Keratoconus is a progressive condition that can severely impact vision, making it critical to diagnose patients before irreversible vision loss occurs. Individuals with risk factors, such as AD of the eyelids, history of eye rubbing, or family history of keratoconus, should be advised to receive routine vision screening for worsening astigmatism, especially during the first few decades of life when keratoconus progresses rapidly.

The conservative management for early keratoconus includes glasses and gas-permeable contact lenses for correction of visual acuity and astigmatism. For advanced keratoconus, scleral lenses often are prescribed. These large-diameter, gas-permeable lenses are designed to rest on the sclera and arch over the entire cornea.⁹ Alternatively, corneal collagen cross-linking is a newer technique that utilizes riboflavin and UVA irradiation to strengthen the corneal tissue. It has proven to be safe and effective in slowing or stopping the progression of keratoconus, particularly when treated at the early stage, and received US Food and Drug Administration approval in 2016.⁹

Glaucoma

Glaucoma is a well-known complication of AD and can lead to irreversible ocular hypertension and optic nerve damage. Corticosteroid use is a major risk factor for glaucoma, and the rise in IOP is thought to be due to increased aqueous outflow resistance.¹⁴

Multiple case reports have linked glaucoma to long-term use of potent topical corticosteroids in the facial and palpebral regions, which has been attributed to direct steroid contact and absorption by ocular tissues, as glaucoma rarely occurs with topical steroid application elsewhere on the body.^15-17 Systemic steroids (ie, prednisolone) taken for more than 8 weeks also have been associated with a marked rise in IOP.¹⁸

Certain risk factors may predispose a steroid user to increased IOP, including existing open-angle glaucoma, diabetes mellitus, collagen disease, and high myopia.^15,19 Steroid responders and younger individuals also demonstrate increased sensitivity to steroids.²⁰

Given that glaucoma often is asymptomatic until advanced stages, early detection is the key for proper intervention. Periodic glaucoma screening by an ophthalmologist would be appropriate for known steroid responders, as well as patients with a prolonged history of topical steroid application in the palpebral region and systemic steroid use, family history of glaucoma, or known ocular pathology.²¹ Furthermore, patients with concurrent glaucoma and AD should be jointly managed by dermatology and ophthalmology, and systemic and topical corticosteroid use should be minimized in favor of alterative agents such as calcineurin inhibitors.²²

In addition to steroid-induced glaucoma, intrinsic atopic glaucoma recently has been proposed as a clinical entity and is characterized by increased inflammatory cytokines—IL-8 and CCL2—in the aqueous humor and abnormal accumulation of fibers in corneoscleral meshwork.²³

Cataracts

Cataracts are estimated to affect 8% to 25% of patients with AD.^21,24 Unlike age-related cataracts, cataracts associated with AD are observed in adolescents and young adults in addition to the older population. The progression of lenticular opacity can rapidly occur and has been reported to coincide with AD flares.^25,26

Patients with AD typically present with anterior or posterior subcapsular cataracts instead of nuclear and cortical cataracts, which are more common in the general population.^27,28 Anterior subcapsular cataracts are more specific to AD, whereas posterior subcapsular cataracts are associated with both prolonged corticosteroid use and AD.²⁶ Children generally are more sensitive to steroids than adults and may develop cataracts more rapidly and at lower concentrations.²⁹

The pathophysiology of cataract formation and progression in the context of AD is multifactorial. Cataract patients with AD have compromised blood-retinal barrier integrity as well as increased oxidative damage in the lens.^30,31 Genetics and blunt trauma from eye rubbing are thought to play a role, and the latter has been associated with faster progression of cataracts.²⁸ In contrast, corticosteroid-induced cataracts likely are caused by transcriptional changes and disrupted osmotic balance in the lens fibers, which can lead to fiber rupture and lens opacification.^26,32 Systemic corticosteroids show the strongest association with cataract development, but inhaled and topical steroids also have been implicated.²⁶

Although cataracts can be surgically corrected, prevention is critical. Patients with early-onset periorbital AD, prolonged use of topical or systemic corticosteroids, and family history of cataracts should be routinely screened. Anterior and posterior subcapsular cataracts are diagnosed with red reflex examinations that can be readily performed by the primary care physician or ophthalmologist.³³ Atopic dermatitis patients with cataracts should be advised to use calcineurin inhibitors and alternative treatments in place of corticosteroids.

Retinal Detachment

Retinal detachment (RD) is a serious complication of AD that can present in individuals younger than 35 years. The incidence of RD in patients with AD has been estimated to be 4% to 8%.³⁴ Retinal detachment manifests with visual disturbances such as flashing lights, shadows, visual field defect, and blurring of vision, but also may occur in the absence of vision changes.^35,36

Across multiple case series, patients who developed RD were consistently found to have AD in the facial or periorbital region and a history of chronic eye rubbing. Multiple patients also presented with concurrent proliferative vitreoretinopathy, lens subluxation, and/or cataracts.^35,37 The mechanism for RD has been attributed to ocular contusion from vigorous eye rubbing, as fundus findings between traumatic and AD-associated RD are similarly characterized by tractional breaks in the retina at vitreous base borders.³⁷

Avoidance of eye rubbing and optimized treatment of facial AD may help prevent RD in patients with AD. Furthermore, all patients with symptoms of RD should be immediately referred to ophthalmology for surgical repair.

Herpetic Ocular Disease

Ocular herpes simplex virus infections cause ocular pain and are associated with notable visual morbidity, as recurrences can result in irreversible corneal scarring and neovascularization. Two retrospective case-control studies independently reported that individuals with a history of AD are at greater risk for herpetic ocular disease compared to age-matched controls.^38,39 Furthermore, atopic disease is associated with higher recurrence rates and slower regeneration of the corneal epithelium.⁴⁰

These findings suggest that AD patients with a history of recurrent herpetic ocular diseases should be closely monitored and treated with antiviral prophylaxis and/or topical corticosteroids, depending on the type of keratitis (epithelial or stromal).⁴⁰ Furthermore, active ocular herpetic infections warrant urgent referral to an ophthalmologist.

Dupilumab-Associated Ocular Complications

Dupilumab, a monoclonal antibody that blocks IL-4 and IL-13 signaling, is the first biologic therapy to be approved for treatment of moderate to severe AD. Prior clinical trials have described a higher incidence of anterior conjunctivitis in dupilumab-treated AD patients (5%–28%) compared to placebo (2%–11%).⁴¹ Of note, the incidence may be as high as 70%, as reported in a recent case series.⁴² Interestingly, independent trials assessing dupilumab treatment in asthma, nasal polyposis, and eosinophilic esophagitis patients did not observe a higher incidence of conjunctivitis in dupilumab-treated patients compared to placebo, suggesting an AD-specific mechanism.⁴³

Prominent features of dupilumab-associated conjunctivitis include hyperemia of the conjunctiva and limbus, in addition to ocular symptoms such as tearing, burning, and bilateral decrease in visual acuity. Marked reduction of conjunctival goblet cells has been reported.⁴⁴ In addition to conjunctivitis, blepharitis also has been reported during dupilumab treatment.⁴⁵

Standardized treatment guidelines for dupilumab-associated ocular complications have not yet been established. Surprisingly, antihistamine eye drops appear to be inefficacious in the treatment of dupilumab-associated conjunctivitis.⁴¹ However, the condition has been successfully managed with topical steroids (fluorometholone ophthalmic suspension 0.1%) and tacrolimus ointment 0.03%.⁴¹ Lifitegrast, an anti-inflammatory agent approved for chronic dry eye, also has been suggested as a treatment option for patients refractory to topical steroids.⁴⁵ Alternatively, cessation of dupilumab could be considered in AD patients who experience severe ocular complications. Atopic dermatitis patients taking dupilumab who have any concerning signs for ocular complications should be referred to an ophthalmologist for further diagnosis and management.

Conclusion

Practicing dermatologists likely will encounter patients with concurrent AD and ocular complications. Although eye examinations are not routinely performed in the care of AD patients, dermatologists can proactively inquire about ocular symptoms and monitor patients longitudinally. Early diagnosis and treatment of these ocular conditions can prevent vision loss in these patients. Furthermore, symptomatic control of AD and careful consideration of the side-effect profiles of medications can potentially reduce the incidence of ocular complications in individuals with AD.

Patients with visual concerns or risk factors, such as a history of vigorous eye rubbing or chronic corticosteroid use, should be jointly managed with an ophthalmologist for optimized care. Moreover, acute exacerbations of ocular symptoms and visual deterioration warrant urgent referral to ophthalmology.

Atopic dermatitis (AD) is a chronic inflammatory skin condition with a lifetime prevalence of 15% to 20% in industrialized countries.¹ It affects both children and adults and is predominantly characterized by a waxing and waning course of eczematous skin lesions and pruritus. In recent years, there is increasing recognition that AD can present with extracutaneous findings. Large-scale epidemiologic studies have reported a notably higher prevalence of ophthalmic complications in the AD population compared to the general population, in a severity-dependent manner.^2,3 Potential complications include blepharitis, keratoconjunctivitis, keratoconus, glaucoma, cataracts, retinal detachment, ophthalmic herpes simplex virus infections, and dupilumab-associated ocular complications.

The etiology of each ocular complication in the context of AD is complex and likely multifactorial. Intrinsic immune dysregulation, physical trauma from eye rubbing, AD medication side effects, and genetics all have been speculated to play a role.² Some of these ocular complications have a chronic course, while others present with sudden onset of symptoms; many of them can result in visual impairment if undiagnosed or left untreated. This article reviews several of the most common ocular comorbidities associated with AD. We discuss the clinical presentation, pathophysiology, and management strategies for each condition.

Blepharitis

Blepharitis, an inflammatory condition of the eyelids, is estimated to affect more than 6% of patients with AD compared to less than 1% of the general population.² Blepharitis can be classified as anterior or posterior, based on the anatomic location of the affected region relative to the lash margin. Affected individuals may experience pruritus and irritation of the eyelids, tearing, a foreign body or burning sensation, crusting of the eyelids, and photophobia.⁴ Anterior blepharitis commonly is due to staphylococcal disease, and posterior blepharitis is secondary to structural changes and obstruction of meibomian gland orifices.

Although the pathophysiology is not well defined, xerosis in atopic patients is accompanied by barrier disruption and transepidermal water loss, which promote eyelid skin inflammation.

The mainstay of therapy for atopic blepharitis consists of conventional lid hygiene regimens, such as warm compresses and gentle scrubbing of the lid margins to remove crust and debris, which can be done with nonprescription cleansers, pads, and baby shampoos. Acute exacerbations may require topical antibiotics (ie, erythromycin or bacitracin applied to the lid margins once daily), topical calcineurin inhibitors (ie, cyclosporine ophthalmic emulsion 0.05%), or low-potency topical corticosteroids (ie, fluorometholone 0.1% or loteprednol etabonate 0.5% ophthalmic suspensions).⁵ Due to potential side effects of medications, especially topical corticosteroids, patients should be referred to ophthalmologists for definitive diagnosis and treatment.

Keratoconjunctivitis

Atopic keratoconjunctivitis (AKC) is a noninfectious inflammatory condition of the cornea and conjunctiva that occurs in an estimated 25% to 42% of patients with AD.^6,7 It frequently presents in late adolescence and has a peak incidence between 30 and 50 years of age.⁸ The symptoms of AKC include ocular pruritus, redness, ropy mucoid discharge, burning discomfort, photophobia, and blurring of vision. Corneal involvement can progress to corneal neovascularization and punctate or macroepithelial erosions and ulcerations, which increase the risk for corneal scarring and visual impairment.⁷

Keratoconjunctivitis is a complex inflammatory disease characterized by infiltration of the conjunctival epithelium by eosinophils, mast cells, and lymphocytes. On examination, patients frequently are found to have concurrent AD of the periorbital skin as well as papillary hypertrophy of the tarsal conjunctiva with accompanying fibrosis, which can lead to entropion (turning inward of the lid margins and lashes) in severe cases.⁷ Ophthalmic evaluation is strongly recommended for patients with AKC to control symptoms, to limit exacerbations, and to prevent sight-threatening inflammation leading to vision loss. Treatment can be challenging given the chronicity of the condition and may require multiple treatment arms. Conservative measures include cool compresses and treatment with ophthalmic eye drops containing antihistamines (ie, ketotifen 0.025% [available over-the-counter]) and mast cell stabilizers (ie, olopatadine ophthalmic solution 0.1%).⁸ Atopic keratoconjunctivitis exacerbations may require short-term use of topical steroids or calcineurin inhibitors, or systemic equivalents for refractory cases.⁶ Long-term maintenance therapy typically consists of proper eye hygiene and steroid-sparing agents that reduce ocular inflammation, such as topical cyclosporine and tacrolimus, neither of which are associated with increased intraocular pressure (IOP)(Figure 1).⁸ Cornea disease resulting from chronic conjunctival/lid microtrauma can be managed with soft or scleral contact lenses.

Keratoconus

Keratoconus is a noninflammatory ocular disorder characterized by progressive thinning and conelike protrusion of the cornea. The corneal topographic changes result in high irregular astigmatism and reduced visual acuity, which can manifest as image blurring or distortion (Figure 2).^2,9 Multiple case series and controlled studies have reported a positive association between keratoconus and a history of atopic disease.^10,11

The precise etiology of keratoconus in the context of AD is unclear and likely is multifactorial. Habitual eye rubbing from periocular pruritus and discomfort has been reported to be a notable contributor to keratoconus.¹² In addition, intrinsic inflammation and imbalance of cytokines and proteases also may contribute to development of keratoconus.¹³

Keratoconus is a progressive condition that can severely impact vision, making it critical to diagnose patients before irreversible vision loss occurs. Individuals with risk factors, such as AD of the eyelids, history of eye rubbing, or family history of keratoconus, should be advised to receive routine vision screening for worsening astigmatism, especially during the first few decades of life when keratoconus progresses rapidly.

The conservative management for early keratoconus includes glasses and gas-permeable contact lenses for correction of visual acuity and astigmatism. For advanced keratoconus, scleral lenses often are prescribed. These large-diameter, gas-permeable lenses are designed to rest on the sclera and arch over the entire cornea.⁹ Alternatively, corneal collagen cross-linking is a newer technique that utilizes riboflavin and UVA irradiation to strengthen the corneal tissue. It has proven to be safe and effective in slowing or stopping the progression of keratoconus, particularly when treated at the early stage, and received US Food and Drug Administration approval in 2016.⁹

Glaucoma

Glaucoma is a well-known complication of AD and can lead to irreversible ocular hypertension and optic nerve damage. Corticosteroid use is a major risk factor for glaucoma, and the rise in IOP is thought to be due to increased aqueous outflow resistance.¹⁴

Multiple case reports have linked glaucoma to long-term use of potent topical corticosteroids in the facial and palpebral regions, which has been attributed to direct steroid contact and absorption by ocular tissues, as glaucoma rarely occurs with topical steroid application elsewhere on the body.^15-17 Systemic steroids (ie, prednisolone) taken for more than 8 weeks also have been associated with a marked rise in IOP.¹⁸

Certain risk factors may predispose a steroid user to increased IOP, including existing open-angle glaucoma, diabetes mellitus, collagen disease, and high myopia.^15,19 Steroid responders and younger individuals also demonstrate increased sensitivity to steroids.²⁰

Given that glaucoma often is asymptomatic until advanced stages, early detection is the key for proper intervention. Periodic glaucoma screening by an ophthalmologist would be appropriate for known steroid responders, as well as patients with a prolonged history of topical steroid application in the palpebral region and systemic steroid use, family history of glaucoma, or known ocular pathology.²¹ Furthermore, patients with concurrent glaucoma and AD should be jointly managed by dermatology and ophthalmology, and systemic and topical corticosteroid use should be minimized in favor of alterative agents such as calcineurin inhibitors.²²

In addition to steroid-induced glaucoma, intrinsic atopic glaucoma recently has been proposed as a clinical entity and is characterized by increased inflammatory cytokines—IL-8 and CCL2—in the aqueous humor and abnormal accumulation of fibers in corneoscleral meshwork.²³

Cataracts

Cataracts are estimated to affect 8% to 25% of patients with AD.^21,24 Unlike age-related cataracts, cataracts associated with AD are observed in adolescents and young adults in addition to the older population. The progression of lenticular opacity can rapidly occur and has been reported to coincide with AD flares.^25,26

Patients with AD typically present with anterior or posterior subcapsular cataracts instead of nuclear and cortical cataracts, which are more common in the general population.^27,28 Anterior subcapsular cataracts are more specific to AD, whereas posterior subcapsular cataracts are associated with both prolonged corticosteroid use and AD.²⁶ Children generally are more sensitive to steroids than adults and may develop cataracts more rapidly and at lower concentrations.²⁹

The pathophysiology of cataract formation and progression in the context of AD is multifactorial. Cataract patients with AD have compromised blood-retinal barrier integrity as well as increased oxidative damage in the lens.^30,31 Genetics and blunt trauma from eye rubbing are thought to play a role, and the latter has been associated with faster progression of cataracts.²⁸ In contrast, corticosteroid-induced cataracts likely are caused by transcriptional changes and disrupted osmotic balance in the lens fibers, which can lead to fiber rupture and lens opacification.^26,32 Systemic corticosteroids show the strongest association with cataract development, but inhaled and topical steroids also have been implicated.²⁶

Although cataracts can be surgically corrected, prevention is critical. Patients with early-onset periorbital AD, prolonged use of topical or systemic corticosteroids, and family history of cataracts should be routinely screened. Anterior and posterior subcapsular cataracts are diagnosed with red reflex examinations that can be readily performed by the primary care physician or ophthalmologist.³³ Atopic dermatitis patients with cataracts should be advised to use calcineurin inhibitors and alternative treatments in place of corticosteroids.

Retinal Detachment

Retinal detachment (RD) is a serious complication of AD that can present in individuals younger than 35 years. The incidence of RD in patients with AD has been estimated to be 4% to 8%.³⁴ Retinal detachment manifests with visual disturbances such as flashing lights, shadows, visual field defect, and blurring of vision, but also may occur in the absence of vision changes.^35,36

Across multiple case series, patients who developed RD were consistently found to have AD in the facial or periorbital region and a history of chronic eye rubbing. Multiple patients also presented with concurrent proliferative vitreoretinopathy, lens subluxation, and/or cataracts.^35,37 The mechanism for RD has been attributed to ocular contusion from vigorous eye rubbing, as fundus findings between traumatic and AD-associated RD are similarly characterized by tractional breaks in the retina at vitreous base borders.³⁷

Avoidance of eye rubbing and optimized treatment of facial AD may help prevent RD in patients with AD. Furthermore, all patients with symptoms of RD should be immediately referred to ophthalmology for surgical repair.

Herpetic Ocular Disease

Ocular herpes simplex virus infections cause ocular pain and are associated with notable visual morbidity, as recurrences can result in irreversible corneal scarring and neovascularization. Two retrospective case-control studies independently reported that individuals with a history of AD are at greater risk for herpetic ocular disease compared to age-matched controls.^38,39 Furthermore, atopic disease is associated with higher recurrence rates and slower regeneration of the corneal epithelium.⁴⁰

These findings suggest that AD patients with a history of recurrent herpetic ocular diseases should be closely monitored and treated with antiviral prophylaxis and/or topical corticosteroids, depending on the type of keratitis (epithelial or stromal).⁴⁰ Furthermore, active ocular herpetic infections warrant urgent referral to an ophthalmologist.

Dupilumab-Associated Ocular Complications

Dupilumab, a monoclonal antibody that blocks IL-4 and IL-13 signaling, is the first biologic therapy to be approved for treatment of moderate to severe AD. Prior clinical trials have described a higher incidence of anterior conjunctivitis in dupilumab-treated AD patients (5%–28%) compared to placebo (2%–11%).⁴¹ Of note, the incidence may be as high as 70%, as reported in a recent case series.⁴² Interestingly, independent trials assessing dupilumab treatment in asthma, nasal polyposis, and eosinophilic esophagitis patients did not observe a higher incidence of conjunctivitis in dupilumab-treated patients compared to placebo, suggesting an AD-specific mechanism.⁴³

Prominent features of dupilumab-associated conjunctivitis include hyperemia of the conjunctiva and limbus, in addition to ocular symptoms such as tearing, burning, and bilateral decrease in visual acuity. Marked reduction of conjunctival goblet cells has been reported.⁴⁴ In addition to conjunctivitis, blepharitis also has been reported during dupilumab treatment.⁴⁵

Standardized treatment guidelines for dupilumab-associated ocular complications have not yet been established. Surprisingly, antihistamine eye drops appear to be inefficacious in the treatment of dupilumab-associated conjunctivitis.⁴¹ However, the condition has been successfully managed with topical steroids (fluorometholone ophthalmic suspension 0.1%) and tacrolimus ointment 0.03%.⁴¹ Lifitegrast, an anti-inflammatory agent approved for chronic dry eye, also has been suggested as a treatment option for patients refractory to topical steroids.⁴⁵ Alternatively, cessation of dupilumab could be considered in AD patients who experience severe ocular complications. Atopic dermatitis patients taking dupilumab who have any concerning signs for ocular complications should be referred to an ophthalmologist for further diagnosis and management.

Conclusion

Practicing dermatologists likely will encounter patients with concurrent AD and ocular complications. Although eye examinations are not routinely performed in the care of AD patients, dermatologists can proactively inquire about ocular symptoms and monitor patients longitudinally. Early diagnosis and treatment of these ocular conditions can prevent vision loss in these patients. Furthermore, symptomatic control of AD and careful consideration of the side-effect profiles of medications can potentially reduce the incidence of ocular complications in individuals with AD.

Patients with visual concerns or risk factors, such as a history of vigorous eye rubbing or chronic corticosteroid use, should be jointly managed with an ophthalmologist for optimized care. Moreover, acute exacerbations of ocular symptoms and visual deterioration warrant urgent referral to ophthalmology.

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease typically with childhood onset. In some cases, the condition persists, but AD usually resolves by the time a child reaches adulthood. Prevalence is difficult to estimate but, in developed countries, is approximately 15% to 30% among children and 2% to 10% among adults.¹

Atopic dermatitis is characterized by chronically itchy dry skin, weeping erythematous papules and plaques, and lichenification. Furthermore, AD often is associated with other atopic diseases, such as food allergy, allergic rhinitis, and bronchial asthma.

In this article, we review the literature on the quality of life (QOL) of patients with AD. Our goals are to discuss the most common methods for measuring QOL in AD and how to use them; highlight specific alterations of QOL in AD; and review data about QOL of children with AD, which is underrepresented in the medical literature, as studies tend to focus on adults. In addition, we address the importance of assessing QOL in patients with AD due to the psychological burden of the disease.

Quality of Life

The harmful effects of AD can include a range of areas, including emotional and mental health, physical activity, social functioning, sleep disturbance, decreased work productivity, financial expenditure, leisure activities, and family relationships. The impact varies by age of the patient, and there are specific instruments for measuring QOL in infants, children, adolescents, and adults.

Because QOL is an important instrument used in many AD studies, we call attention to the work of the Harmonising Outcome Measures for Eczema (HOME) initiative, which established a core outcome set for all AD clinical trials to enable comparison of results of individual studies.² Quality of life was identified in HOME as one of 4 basic outcome measures that should be included in every AD trial (the others are clinician-reported signs, patient-reported symptoms, and long-term control).³ According to the recent agreement, the following QOL instruments should be used: Dermatology Life Quality Index (DLQI) for adults, Children’s Dermatology Life Quality Index (CDLQI) for children, and Infants’ Dermatitis Quality of Life Index (IDQOL) for infants.⁴

In dermatology, these instruments can be divided into 3 basic categories: generic, dermatology specific, and disease specific.⁵ Generic QOL questionnaires are beneficial when comparing the QOL of an AD patient to patients with other conditions or to healthy individuals. On the other hand, dermatology-specific and AD-specific methods are more effective instruments for detecting impairments linked directly to the disease and, therefore, are more sensitive to changes in QOL.⁵ Some of the most frequently used QOL measures^5,6 for AD along with their key attributes are listed in the Table.

In contrast, several other methods that also are administered by a parent/guardian assess how the parent perceives the QOL of their child with AD; these methods are essential for small children and infants who cannot answer questions themselves. The IDQOL⁹ was designed to assess the QOL of patients younger than 4 years using a parent-completed questionnaire. For older children and adolescents aged 4 to 16 years, the CDLQI¹⁰ is a widely used instrument; the questionnaire is completed by the child and is available in a cartoon format.¹⁰

For patients older than 16 years, 2 important instruments are the DLQI, a generic dermatology instrument, and the Quality of Life Index for Atopic Dermatitis (QoLIAD).¹¹

Clearly it can be troublesome for researchers and clinicians to find the most suitable instrument to evaluate QOL in AD patients. To make this task easier, the European Academy of Dermatology and Venereology Task Force released a position paper with the following recommendations: (1) only validated instruments should be used, and (2) their use should be based on the age of the patients for which the instruments were designed. It is reommended that researchers use a combination of a generic and a dermatology-specific or AD-specific instrument, whereas clinicians should apply a dermatology-specific or AD-specific method, or both.⁵

Alterations of QOL in AD

Sleep Disturbance in AD
Sleep disorders observed in AD include difficulty falling asleep, frequent waking episodes, shorter sleep duration, and feelings of inadequate sleep, which often result in impairment of daily activity.^12,13 Correlation has been found between sleep quality and QOL in both children and adults.¹⁴ Approximately 60% of children affected by AD experience a sleep disturbance,¹⁵ which seems to correlate well with disease severity.¹⁶ A US study found that adults with AD are more likely to experience a sleep disturbance, which often affects daytime functioning and work productivity.¹³

Financial Aspects and Impact on Work
The financial burden of AD is extensive.¹⁷ There are direct medical costs, including medication, visits to the physician, alternative therapies, and nonprescription products. Patients tend to spend relevant money on such items as moisturizers, bath products, antihistamines, topical steroids, and topical antibiotics.^18,19 However, it seems that most of the cost of AD is due to indirect and nonmedical costs, including transportation to medical visits; loss of work days; extra childcare; and expenditures associated with lifestyle changes,^19,20 such as modifying diet, wearing special clothes, using special bed linens, and purchasing special household items (eg, anti–dust mite vacuum cleaner, humidifier, new carpeting).^17,19

Absenteeism from work often is a consequence of physician appointments; in addition, parents/guardians of a child with AD often miss work due to medical care. Even at work, patients (or parents/guardians) often experience decreased work productivity (so-called presenteeism) due to loss of sleep and anxiety.²¹ In addressing the effects of AD on work life, a systematic literature review found that AD strongly affects sick leave and might have an impact on job choice and change or loss of job.²²

Furthermore, according to Su et al,²³ the costs of AD are related to disease severity. Moreover, their data suggest that among chronic childhood diseases, the financial burden of AD is greater than the cost of asthma and similar to the cost of diabetes mellitus.²³

Association Between QOL and Disease Severity

A large observational study found that improvement in AD severity was followed by an increase in QOL.²⁴ A positive correlation between disease severity and QOL has been found in other studies,^25,26 though no correlation or only moderate correlation also has been reported.²⁷ Apparently, in addition to QOL, disease severity scores are substantial parameters in the evaluation of distress caused by AD; the HOME initiative has identified clinician-reported signs and patient-reported symptoms as 2 of 4 core outcomes domains to include in all future AD clinical trials.³ For measuring symptoms, the Patient-Oriented Eczema Measure (POEM) is the recommended instrument.²⁸ Regarding clinical signs, the HOME group named the Eczema Area and Severity Index (EASI) as the preferred instrument.²⁹

Psychological Burden

Stress is a triggering factor for AD, but the connection between skin and mind appears bidirectional. The biological reaction to stress probably lowers the itch threshold and disrupts the skin barrier.³⁰ The Global Burden of Disease Study showed that skin diseases are the fourth leading cause of nonfatal disease burden.³¹ There are several factors—pruritus, scratch, and pain—that can all lead to sleep deprivation and daytime fatigue. Based on our experience, if lesions develop on visible areas, patients can feel stigmatized, which restricts their social life.

The most common psychological comorbidities of AD are anxiety and depression. In a cross-sectional, multicenter study, there was a significantly higher prevalence of depression (P<.001) and anxiety disorder (P=.02) among patients with common skin diseases compared to a control group.³² In a study that assessed AD patients, researchers found a higher risk of depression and anxiety.³³ Suicidal ideation also is more common in the population with AD^32,34; a study showed that the risk of suicidal ideation in adolescents was nearly 4-fold in patients with itching skin lesions compared to those without itch.³⁴

According to Linnet and Jemec,³⁵ mental and psychological comorbidities of AD are associated with lower QOL, not with clinical severity. As a result, to improve QOL in AD, one should take care of both dermatological and psychological problems. It has been demonstrated that psychological interventions, such as autogenic training, cognitive-behavioral therapy, relaxation techniques, habit reversal training,³⁶ and hypnotherapy³⁷ might be helpful in individual cases; educational interventions also are recommended.³⁶ With these adjuvant therapies, psychological status, unpleasant clinical symptoms, and QOL could be improved, though further studies are needed to confirm these benefits.

Conclusion

Atopic dermatitis places a notable burden on patients and their families. The degree of burden is probably related to disease severity. For measuring QOL, researchers and clinicians should use validated methods suited to the age of the patients for which they were designed. More studies are needed to assess the effects of different treatments on QOL. Besides pharmacotherapy, psychotherapy and educational programs might be beneficial for improving QOL, another important area to be studied.

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease typically with childhood onset. In some cases, the condition persists, but AD usually resolves by the time a child reaches adulthood. Prevalence is difficult to estimate but, in developed countries, is approximately 15% to 30% among children and 2% to 10% among adults.¹

Atopic dermatitis is characterized by chronically itchy dry skin, weeping erythematous papules and plaques, and lichenification. Furthermore, AD often is associated with other atopic diseases, such as food allergy, allergic rhinitis, and bronchial asthma.

In this article, we review the literature on the quality of life (QOL) of patients with AD. Our goals are to discuss the most common methods for measuring QOL in AD and how to use them; highlight specific alterations of QOL in AD; and review data about QOL of children with AD, which is underrepresented in the medical literature, as studies tend to focus on adults. In addition, we address the importance of assessing QOL in patients with AD due to the psychological burden of the disease.

Quality of Life

The harmful effects of AD can include a range of areas, including emotional and mental health, physical activity, social functioning, sleep disturbance, decreased work productivity, financial expenditure, leisure activities, and family relationships. The impact varies by age of the patient, and there are specific instruments for measuring QOL in infants, children, adolescents, and adults.

Because QOL is an important instrument used in many AD studies, we call attention to the work of the Harmonising Outcome Measures for Eczema (HOME) initiative, which established a core outcome set for all AD clinical trials to enable comparison of results of individual studies.² Quality of life was identified in HOME as one of 4 basic outcome measures that should be included in every AD trial (the others are clinician-reported signs, patient-reported symptoms, and long-term control).³ According to the recent agreement, the following QOL instruments should be used: Dermatology Life Quality Index (DLQI) for adults, Children’s Dermatology Life Quality Index (CDLQI) for children, and Infants’ Dermatitis Quality of Life Index (IDQOL) for infants.⁴

In dermatology, these instruments can be divided into 3 basic categories: generic, dermatology specific, and disease specific.⁵ Generic QOL questionnaires are beneficial when comparing the QOL of an AD patient to patients with other conditions or to healthy individuals. On the other hand, dermatology-specific and AD-specific methods are more effective instruments for detecting impairments linked directly to the disease and, therefore, are more sensitive to changes in QOL.⁵ Some of the most frequently used QOL measures^5,6 for AD along with their key attributes are listed in the Table.

In contrast, several other methods that also are administered by a parent/guardian assess how the parent perceives the QOL of their child with AD; these methods are essential for small children and infants who cannot answer questions themselves. The IDQOL⁹ was designed to assess the QOL of patients younger than 4 years using a parent-completed questionnaire. For older children and adolescents aged 4 to 16 years, the CDLQI¹⁰ is a widely used instrument; the questionnaire is completed by the child and is available in a cartoon format.¹⁰

For patients older than 16 years, 2 important instruments are the DLQI, a generic dermatology instrument, and the Quality of Life Index for Atopic Dermatitis (QoLIAD).¹¹

Clearly it can be troublesome for researchers and clinicians to find the most suitable instrument to evaluate QOL in AD patients. To make this task easier, the European Academy of Dermatology and Venereology Task Force released a position paper with the following recommendations: (1) only validated instruments should be used, and (2) their use should be based on the age of the patients for which the instruments were designed. It is reommended that researchers use a combination of a generic and a dermatology-specific or AD-specific instrument, whereas clinicians should apply a dermatology-specific or AD-specific method, or both.⁵

Alterations of QOL in AD

Sleep Disturbance in AD
Sleep disorders observed in AD include difficulty falling asleep, frequent waking episodes, shorter sleep duration, and feelings of inadequate sleep, which often result in impairment of daily activity.^12,13 Correlation has been found between sleep quality and QOL in both children and adults.¹⁴ Approximately 60% of children affected by AD experience a sleep disturbance,¹⁵ which seems to correlate well with disease severity.¹⁶ A US study found that adults with AD are more likely to experience a sleep disturbance, which often affects daytime functioning and work productivity.¹³

Financial Aspects and Impact on Work
The financial burden of AD is extensive.¹⁷ There are direct medical costs, including medication, visits to the physician, alternative therapies, and nonprescription products. Patients tend to spend relevant money on such items as moisturizers, bath products, antihistamines, topical steroids, and topical antibiotics.^18,19 However, it seems that most of the cost of AD is due to indirect and nonmedical costs, including transportation to medical visits; loss of work days; extra childcare; and expenditures associated with lifestyle changes,^19,20 such as modifying diet, wearing special clothes, using special bed linens, and purchasing special household items (eg, anti–dust mite vacuum cleaner, humidifier, new carpeting).^17,19

Absenteeism from work often is a consequence of physician appointments; in addition, parents/guardians of a child with AD often miss work due to medical care. Even at work, patients (or parents/guardians) often experience decreased work productivity (so-called presenteeism) due to loss of sleep and anxiety.²¹ In addressing the effects of AD on work life, a systematic literature review found that AD strongly affects sick leave and might have an impact on job choice and change or loss of job.²²

Furthermore, according to Su et al,²³ the costs of AD are related to disease severity. Moreover, their data suggest that among chronic childhood diseases, the financial burden of AD is greater than the cost of asthma and similar to the cost of diabetes mellitus.²³

Association Between QOL and Disease Severity

A large observational study found that improvement in AD severity was followed by an increase in QOL.²⁴ A positive correlation between disease severity and QOL has been found in other studies,^25,26 though no correlation or only moderate correlation also has been reported.²⁷ Apparently, in addition to QOL, disease severity scores are substantial parameters in the evaluation of distress caused by AD; the HOME initiative has identified clinician-reported signs and patient-reported symptoms as 2 of 4 core outcomes domains to include in all future AD clinical trials.³ For measuring symptoms, the Patient-Oriented Eczema Measure (POEM) is the recommended instrument.²⁸ Regarding clinical signs, the HOME group named the Eczema Area and Severity Index (EASI) as the preferred instrument.²⁹

Psychological Burden

Stress is a triggering factor for AD, but the connection between skin and mind appears bidirectional. The biological reaction to stress probably lowers the itch threshold and disrupts the skin barrier.³⁰ The Global Burden of Disease Study showed that skin diseases are the fourth leading cause of nonfatal disease burden.³¹ There are several factors—pruritus, scratch, and pain—that can all lead to sleep deprivation and daytime fatigue. Based on our experience, if lesions develop on visible areas, patients can feel stigmatized, which restricts their social life.

The most common psychological comorbidities of AD are anxiety and depression. In a cross-sectional, multicenter study, there was a significantly higher prevalence of depression (P<.001) and anxiety disorder (P=.02) among patients with common skin diseases compared to a control group.³² In a study that assessed AD patients, researchers found a higher risk of depression and anxiety.³³ Suicidal ideation also is more common in the population with AD^32,34; a study showed that the risk of suicidal ideation in adolescents was nearly 4-fold in patients with itching skin lesions compared to those without itch.³⁴

According to Linnet and Jemec,³⁵ mental and psychological comorbidities of AD are associated with lower QOL, not with clinical severity. As a result, to improve QOL in AD, one should take care of both dermatological and psychological problems. It has been demonstrated that psychological interventions, such as autogenic training, cognitive-behavioral therapy, relaxation techniques, habit reversal training,³⁶ and hypnotherapy³⁷ might be helpful in individual cases; educational interventions also are recommended.³⁶ With these adjuvant therapies, psychological status, unpleasant clinical symptoms, and QOL could be improved, though further studies are needed to confirm these benefits.

Conclusion

Atopic dermatitis places a notable burden on patients and their families. The degree of burden is probably related to disease severity. For measuring QOL, researchers and clinicians should use validated methods suited to the age of the patients for which they were designed. More studies are needed to assess the effects of different treatments on QOL. Besides pharmacotherapy, psychotherapy and educational programs might be beneficial for improving QOL, another important area to be studied.

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease typically with childhood onset. In some cases, the condition persists, but AD usually resolves by the time a child reaches adulthood. Prevalence is difficult to estimate but, in developed countries, is approximately 15% to 30% among children and 2% to 10% among adults.¹

Atopic dermatitis is characterized by chronically itchy dry skin, weeping erythematous papules and plaques, and lichenification. Furthermore, AD often is associated with other atopic diseases, such as food allergy, allergic rhinitis, and bronchial asthma.

In this article, we review the literature on the quality of life (QOL) of patients with AD. Our goals are to discuss the most common methods for measuring QOL in AD and how to use them; highlight specific alterations of QOL in AD; and review data about QOL of children with AD, which is underrepresented in the medical literature, as studies tend to focus on adults. In addition, we address the importance of assessing QOL in patients with AD due to the psychological burden of the disease.

Quality of Life

The harmful effects of AD can include a range of areas, including emotional and mental health, physical activity, social functioning, sleep disturbance, decreased work productivity, financial expenditure, leisure activities, and family relationships. The impact varies by age of the patient, and there are specific instruments for measuring QOL in infants, children, adolescents, and adults.

Because QOL is an important instrument used in many AD studies, we call attention to the work of the Harmonising Outcome Measures for Eczema (HOME) initiative, which established a core outcome set for all AD clinical trials to enable comparison of results of individual studies.² Quality of life was identified in HOME as one of 4 basic outcome measures that should be included in every AD trial (the others are clinician-reported signs, patient-reported symptoms, and long-term control).³ According to the recent agreement, the following QOL instruments should be used: Dermatology Life Quality Index (DLQI) for adults, Children’s Dermatology Life Quality Index (CDLQI) for children, and Infants’ Dermatitis Quality of Life Index (IDQOL) for infants.⁴

In dermatology, these instruments can be divided into 3 basic categories: generic, dermatology specific, and disease specific.⁵ Generic QOL questionnaires are beneficial when comparing the QOL of an AD patient to patients with other conditions or to healthy individuals. On the other hand, dermatology-specific and AD-specific methods are more effective instruments for detecting impairments linked directly to the disease and, therefore, are more sensitive to changes in QOL.⁵ Some of the most frequently used QOL measures^5,6 for AD along with their key attributes are listed in the Table.

In contrast, several other methods that also are administered by a parent/guardian assess how the parent perceives the QOL of their child with AD; these methods are essential for small children and infants who cannot answer questions themselves. The IDQOL⁹ was designed to assess the QOL of patients younger than 4 years using a parent-completed questionnaire. For older children and adolescents aged 4 to 16 years, the CDLQI¹⁰ is a widely used instrument; the questionnaire is completed by the child and is available in a cartoon format.¹⁰

For patients older than 16 years, 2 important instruments are the DLQI, a generic dermatology instrument, and the Quality of Life Index for Atopic Dermatitis (QoLIAD).¹¹

Clearly it can be troublesome for researchers and clinicians to find the most suitable instrument to evaluate QOL in AD patients. To make this task easier, the European Academy of Dermatology and Venereology Task Force released a position paper with the following recommendations: (1) only validated instruments should be used, and (2) their use should be based on the age of the patients for which the instruments were designed. It is reommended that researchers use a combination of a generic and a dermatology-specific or AD-specific instrument, whereas clinicians should apply a dermatology-specific or AD-specific method, or both.⁵

Alterations of QOL in AD

Sleep Disturbance in AD
Sleep disorders observed in AD include difficulty falling asleep, frequent waking episodes, shorter sleep duration, and feelings of inadequate sleep, which often result in impairment of daily activity.^12,13 Correlation has been found between sleep quality and QOL in both children and adults.¹⁴ Approximately 60% of children affected by AD experience a sleep disturbance,¹⁵ which seems to correlate well with disease severity.¹⁶ A US study found that adults with AD are more likely to experience a sleep disturbance, which often affects daytime functioning and work productivity.¹³

Financial Aspects and Impact on Work
The financial burden of AD is extensive.¹⁷ There are direct medical costs, including medication, visits to the physician, alternative therapies, and nonprescription products. Patients tend to spend relevant money on such items as moisturizers, bath products, antihistamines, topical steroids, and topical antibiotics.^18,19 However, it seems that most of the cost of AD is due to indirect and nonmedical costs, including transportation to medical visits; loss of work days; extra childcare; and expenditures associated with lifestyle changes,^19,20 such as modifying diet, wearing special clothes, using special bed linens, and purchasing special household items (eg, anti–dust mite vacuum cleaner, humidifier, new carpeting).^17,19

Absenteeism from work often is a consequence of physician appointments; in addition, parents/guardians of a child with AD often miss work due to medical care. Even at work, patients (or parents/guardians) often experience decreased work productivity (so-called presenteeism) due to loss of sleep and anxiety.²¹ In addressing the effects of AD on work life, a systematic literature review found that AD strongly affects sick leave and might have an impact on job choice and change or loss of job.²²

Furthermore, according to Su et al,²³ the costs of AD are related to disease severity. Moreover, their data suggest that among chronic childhood diseases, the financial burden of AD is greater than the cost of asthma and similar to the cost of diabetes mellitus.²³

Association Between QOL and Disease Severity

A large observational study found that improvement in AD severity was followed by an increase in QOL.²⁴ A positive correlation between disease severity and QOL has been found in other studies,^25,26 though no correlation or only moderate correlation also has been reported.²⁷ Apparently, in addition to QOL, disease severity scores are substantial parameters in the evaluation of distress caused by AD; the HOME initiative has identified clinician-reported signs and patient-reported symptoms as 2 of 4 core outcomes domains to include in all future AD clinical trials.³ For measuring symptoms, the Patient-Oriented Eczema Measure (POEM) is the recommended instrument.²⁸ Regarding clinical signs, the HOME group named the Eczema Area and Severity Index (EASI) as the preferred instrument.²⁹

Psychological Burden

Stress is a triggering factor for AD, but the connection between skin and mind appears bidirectional. The biological reaction to stress probably lowers the itch threshold and disrupts the skin barrier.³⁰ The Global Burden of Disease Study showed that skin diseases are the fourth leading cause of nonfatal disease burden.³¹ There are several factors—pruritus, scratch, and pain—that can all lead to sleep deprivation and daytime fatigue. Based on our experience, if lesions develop on visible areas, patients can feel stigmatized, which restricts their social life.

The most common psychological comorbidities of AD are anxiety and depression. In a cross-sectional, multicenter study, there was a significantly higher prevalence of depression (P<.001) and anxiety disorder (P=.02) among patients with common skin diseases compared to a control group.³² In a study that assessed AD patients, researchers found a higher risk of depression and anxiety.³³ Suicidal ideation also is more common in the population with AD^32,34; a study showed that the risk of suicidal ideation in adolescents was nearly 4-fold in patients with itching skin lesions compared to those without itch.³⁴

According to Linnet and Jemec,³⁵ mental and psychological comorbidities of AD are associated with lower QOL, not with clinical severity. As a result, to improve QOL in AD, one should take care of both dermatological and psychological problems. It has been demonstrated that psychological interventions, such as autogenic training, cognitive-behavioral therapy, relaxation techniques, habit reversal training,³⁶ and hypnotherapy³⁷ might be helpful in individual cases; educational interventions also are recommended.³⁶ With these adjuvant therapies, psychological status, unpleasant clinical symptoms, and QOL could be improved, though further studies are needed to confirm these benefits.

Conclusion

Atopic dermatitis places a notable burden on patients and their families. The degree of burden is probably related to disease severity. For measuring QOL, researchers and clinicians should use validated methods suited to the age of the patients for which they were designed. More studies are needed to assess the effects of different treatments on QOL. Besides pharmacotherapy, psychotherapy and educational programs might be beneficial for improving QOL, another important area to be studied.

Fecal incontinence (FI), also known as accidental bowel leakage, is the involuntary loss of feces, which includes both liquid and solid stool as defined by the International Continence Society (ICS) and the International Urogynecological Association (IUGA).^1,2 Fecal incontinence is common, occurring in 7% to 25% of community-dwelling women, and it increases with age.^2-6 The condition is rarely addressed, with only 30% of women seeking care.^6-8 This is due to patient embarrassment and the lack of a reliable screening tool. However, FI affects quality of life and mental health, and the associated economic burden likely will rise given the increased prevalence of FI among older women.^2,4,7,9

Fecal incontinence occurs due to poor stool consistency, anal and pelvic muscle weakness, reduced rectal compliance, reduced or increased rectal sensation, or bowel inflammation or dysfunction. Many conditions can cause FI (TABLE 1).^5,10,11 It is therefore important to elicit a full medical history with a focus on specific bowel symptoms, such as stool consistency type (TABLE 2),¹² FI frequency, and duration of symptoms, as well as to perform a complete examination to identify any readily reversible or malignant causes. A colonoscopy is recommended for individuals who meet screening criteria or present with a change in bowel symptoms, such as diarrhea, bleeding, or obstruction.^13,14

Fecal incontinence treatments include a range of approaches categorized from conservative, or first-line therapy, to fourth-line surgical managements (FIGURE 1).^1,10,13,14 In this Update, we review the results of 3 well-designed trials that enrolled women with frequent nonneurogenic FI. 

Common first- and second-line treatments produce equivalent improvements in FI symptoms at
6 months 

Jelovsek JE, Markland AD, Whitehead WE, et al; National Institute of Child Health and Human Development Pelvic Floor Disorders Network. Controlling faecal incontinence in women by performing anal exercises with biofeedback or loperamide: a randomized clinical trial. Lancet Gastroenterol Hepatol. 2019;4:698-710. 

In a multicenter, randomized trial of first- and second-line treatments for FI, Jelovsek and colleagues evaluated the efficacy of oral placebo, loperamide, pelvic floor physical therapy (PFPT) with biofeedback using anorectal manometry, or combination therapy over a 24-week period. 

Continue to: Four treatments compared...

Three hundred women with FI occurring monthly for 3 months were included in the trial. Women were excluded if they had a stool classification of type 1 or type 7 on the Bristol Stool Scale, inflammatory bowel disease (IBD), history of rectovaginal fistula or cloacal defect, rectal prolapse, prior bowel diversion, fecal impaction, neurologic disorder leading to incontinence, use of loperamide or diphenoxylate within the last 30 days, childbirth within the last 3 months, need for antiretroviral drugs, hepatic impairment, or chronic abdominal pain without diarrhea. 

Baseline characteristics and symptoms severity were similar among participants. The average age of the women was 63 years, with 79% white and 85% postmenopausal. Participants had a mean (SD) of 1.6 (1.8) leaks per day. 

Participants were randomly assigned in a 0.5:1:1:1 fashion to receive oral placebo, loperamide, oral placebo with PFPT/biofeedback, or loperamide with PFPT/biofeedback. All participants received a standardized educational pamphlet that outlined dietary and behavioral recommendations. 

Women assigned to PFPT/biofeedback received 6 sessions every other week. Loperamide was started at a dosage of 2 mg per day with the possibility of dose maintenance, escalation, reduction, or discontinuation. 

Study outcomes. The primary outcome was a change from baseline to 24 weeks in the Vaizey FI symptom severity score, which assesses fecal frequency, urgency, and use of pads and medications. Secondary outcomes included assessment of a 7-day bowel diary and other quality-of-life measures. Data at 24 weeks were available for 89% of the women. 

All treatment groups experienced improved FI symptoms 

Based on changes in Vaizey scores after 24 weeks of treatment, women in all treatment groups had similar improvement in symptoms severity. However, those who received loperamide and PFPT/biofeedback had decreased pad changes per week and more accident-free days compared with women treated with placebo and biofeedback. Quality of life at 24 weeks was not statistically different between treatment groups as improvement was seen in all groups, including those who received oral placebo and patient education. 

Adverse events. The proportion of gastrointestinal adverse effects was similar between treatment groups, ranging from 45% to 63%. Constipation was the most common adverse event overall and was more common in those taking loperamide, occurring in 51% of the loperamide plus PFPT/biofeedback group, 38% of those who received loperamide alone, 23% of the biofeedback with placebo group, and 12% of the placebo-alone group. 

Strengths and limitations. Strengths of this study include its multisite, large sample size, low dropout rate, and sufficiently powered design to compare various combinations of first- and second-line therapies in women with a mean baseline FI of 1.6 leaks per day. Another strength is the robustness of the PFPT/biofeedback sessions that used anorectal manometry. This may, however, limit the study's external validity given that clinical use of this device is likely rare. Additionally, the population was comprised largely of postmenopausal and white women, which may make the findings less generalizable to other populations. 

Continue to: Novel vaginal bowel control system...

Novel vaginal bowel control system is effective, durable over 12 months for FI treatment 

Richter HE, Dunivan G, Brown HW, et al. A 12-month clinical durability of effectiveness and safety evaluation of a vaginal bowel control system for the nonsurgical treatment of fecal incontinence. Female Pelvic Med Reconstr Surg. 2019;25:113-119. 

Richter and colleagues characterized clinical success, effect on quality of life, and durability over 12 months of a novel vaginal bowel control device (Eclipse System; Pelvalon) for FI in a prospective cohort study. The device is a silicone-coated vaginal insert with a detachable pump and balloon that deflects the rectovaginal septum posteriorly, thus impeding the passage of stool in the rectum (FIGURE 2). 

Study eligibility criteria and treatment protocol 

Women were eligible for the study if they had 4 or more episodes of fecal soiling on a 2-week bowel diary and had FI for at least 6 months. Participants were excluded if they had prolapse outside the hymen, rectovaginal fistula, IBD, congenital anorectal malformation, urinary or colorectal infection, chronic pelvic or anorectal pain, pregnancy or planning pregnancy in the next 5 months, unmanaged chronic watery diarrhea, presence of an open wound or tear in the vagina, significant urogenital atrophy, or any psychiatric or neurologic disorder that would hinder the ability to participate. 

Participants successfully fitted with the device (3 attempts were allowed) were entered into the study's run-in phase. Those who were successfully fitted and had a 50% or greater reduction in FI continued into the treatment phase with 12 months of follow-up. 

Of the 137 women eligible for device fitting, 62% were successfully fitted. The 73 (86%) women who had a 50% or greater reduction in FI during the run-in period comprised the intent-to-treat study population. On average, these women were 61.3 years of age, with 70% white and 82% postmenopausal. At baseline, they had a mean of 14.1 episodes of FI over 2 weeks. (Prior to enrollment, 97.3% of women attempted self-management strategies, 17.8% to 23% failed conservative therapy, and 7.8% to 13.7% failed surgical therapy.) The follow-up rate at 12 months was 74%. 

Study outcomes. The primary outcome was treatment success, defined as proportion of subjects with a 50% or greater reduction in FI episodes at 3 months; this outcome also was evaluated at 6 and 12 months. Secondary outcomes were the number of FI episodes and quality-of-life measures at 3, 6, and 12 months. 

Treatment success, patient satisfaction high 

In the treatment phase, women had sustained improvements in symptom severity and quality-of-life measures over 12 months. Treatment success was 73% at 3 months, 71% at 6 months, and 70% at 12 months. Complete continence was achieved in 46% of participants at 12 months, and major FI episodes (requiring immediate change of undergarments) decreased from 5.0 at baseline to 0.5 at 12 months. Quality-of-life measures were improved at 3 months, and improvement was sustained over 12 months. Satisfaction was 94% at 12 months. 

Adverse events. No serious device-related adverse events occurred. Mild device-related adverse events were experienced by 45% of women during the fitting process and by 38% during treatment period. These included vaginal wall injury such as hyperemia and erosion; vaginal or pelvic discomfort; vaginal infection; constipation; and lower urinary tract issues such as urinary tract infection, urinary incontinence, and voiding dysfunction. No adverse events led to treatment discontinuation. 

Strengths and limitations. Strengths of this study include that it was conducted at multiple clinical sites, had a large sample size, and had a 1-year follow-up period in a population with daily FI. A limitation was that only women who had a 50% or greater reduction in FI episodes during the run-in period were followed for 12 months; however, this was 86% of the original cohort. The use of a comparative group using other devices, such as anal plugs, would have strengthened this study. 

Continue to: Sacroneuromodulation for FI…

Sacral neuromodulation for FI is effective long-term 

Hull T, Giese C, Wexner SD, et al; for the SNS Study Group. Long-term durability of sacral nerve stimulation therapy for chronic fecal incontinence. Dis Colon Rectum. 2013;56:234-245. 

In this multicenter, prospective cohort study, Hull and colleagues evaluated the 5-year efficacy of sacral neuromodulation (SNM), also known as sacral nerve stimulation, for treatment of FI. This study followed an earlier investigation by Wexner and colleagues, which reported that 83% of 120 patients treated with SNM had a 50% or greater improvement in FI episodes at 12 months.¹⁶ 

Details of the study 

The investigators enrolled 133 participants (92% female) who had more than 2 episodes of FI per week for longer than 6 months (12 months after vaginal delivery). Participants were excluded if they had congenital anorectal malformations, prior rectal surgery within the past 12 months (or 24 months if due to cancer), defects greater than 120° of the external anal sphincter (EAS), IBD, unmanaged chronic watery diarrhea, stool consistency type 6 or type 7 on the Bristol Stool Scale, sequela of pelvic radiation, active anal abscess or fistula, pregnancy, or planned pregnancy. 

Eligible participants underwent a 2-stage procedure with the InterStim bowel control device (Medtronic). If participants experienced a 50% or greater reduction in incontinence episodes with a wearable external SNM device in the test stimulation (stage 1), they received the chronic SNM implant device (stage 2). 

Participants who underwent device implantation were followed at 1, 3, and 6 months and annually for 5 years or until they exited the study. Bowel diaries and quality of life assessments were completed at baseline and at follow-up. 

The primary outcome was therapeutic success, defined as 50% or greater improvement in FI episodes per week. 

A total of 120 participants (90%) underwent implantation of the chronic lead and neuromodulator, and 76 (63%) were followed for 5 years. Baseline characteristics available in the initial study of 133 participants showed that the mean age was 60.5 years; 25% had undergone a prior anal sphincteroplasty; and 16.5% and 10.5% had EAS or internal anal sphincter (IAS) defects, respectively, on endoanal ultrasonography.¹⁶ 

Therapeutic success was high at 5 years 

At the 5-year follow-up, 89% (64/72) of participants met therapeutic success, with a reduction in weekly FI episodes from 9.1 at baseline to 1.7 at 5 years. The number of incontinence pads required decreased, and more participants wore no pads at 5 years. In the intention-to-treat analysis, carrying forward the baseline FI rate in participants who lacked follow-up data, the therapeutic success rate was 69%. Quality-of-life measures improved at 5 years, both statistically and by minimal clinical difference. 

Adverse events. Sixty-eight percent of participants experienced device-related adverse events, including implant site pain, change in sensation of stimulation, change in efficacy, implant site infection, or neurostimulator battery depletion (neurostimulator use commonly expires after 3 to 5 years). Of these events, 80% were successfully treated with medications, reprogramming, or no intervention. The 5-year probability of device revision or replacement was 24.4%, and the 5-year probability of device explant was 19.0%. 

Strengths and limitations. Overall, this study was a well-designed, multicenter trial with long-term follow-up that showed significant improvement in FI with the use of SNM. Its strengths include the enrollment of postmenopausal women who had current defects in EAS and/or IAS on endoanal ultrasonography and 25% who had a prior sphincteroplasty. The findings therefore are relevant to the gynecologic population in whom anal sphincteroplasty would not be recommended. The study also accounted for dropouts and reported the adjusted success rate of 69% at 5 years in that group. 

The lack of a control arm to rule out the placebo effect is a limitation of this study, although randomized trials comparing the effect of SNM "on" versus "off" showed greater improvement with the device "on."¹⁷ 

Fecal incontinence (FI), also known as accidental bowel leakage, is the involuntary loss of feces, which includes both liquid and solid stool as defined by the International Continence Society (ICS) and the International Urogynecological Association (IUGA).^1,2 Fecal incontinence is common, occurring in 7% to 25% of community-dwelling women, and it increases with age.^2-6 The condition is rarely addressed, with only 30% of women seeking care.^6-8 This is due to patient embarrassment and the lack of a reliable screening tool. However, FI affects quality of life and mental health, and the associated economic burden likely will rise given the increased prevalence of FI among older women.^2,4,7,9

Fecal incontinence occurs due to poor stool consistency, anal and pelvic muscle weakness, reduced rectal compliance, reduced or increased rectal sensation, or bowel inflammation or dysfunction. Many conditions can cause FI (TABLE 1).^5,10,11 It is therefore important to elicit a full medical history with a focus on specific bowel symptoms, such as stool consistency type (TABLE 2),¹² FI frequency, and duration of symptoms, as well as to perform a complete examination to identify any readily reversible or malignant causes. A colonoscopy is recommended for individuals who meet screening criteria or present with a change in bowel symptoms, such as diarrhea, bleeding, or obstruction.^13,14

Fecal incontinence treatments include a range of approaches categorized from conservative, or first-line therapy, to fourth-line surgical managements (FIGURE 1).^1,10,13,14 In this Update, we review the results of 3 well-designed trials that enrolled women with frequent nonneurogenic FI. 

Common first- and second-line treatments produce equivalent improvements in FI symptoms at
6 months 

Jelovsek JE, Markland AD, Whitehead WE, et al; National Institute of Child Health and Human Development Pelvic Floor Disorders Network. Controlling faecal incontinence in women by performing anal exercises with biofeedback or loperamide: a randomized clinical trial. Lancet Gastroenterol Hepatol. 2019;4:698-710. 

In a multicenter, randomized trial of first- and second-line treatments for FI, Jelovsek and colleagues evaluated the efficacy of oral placebo, loperamide, pelvic floor physical therapy (PFPT) with biofeedback using anorectal manometry, or combination therapy over a 24-week period. 

Continue to: Four treatments compared...

Three hundred women with FI occurring monthly for 3 months were included in the trial. Women were excluded if they had a stool classification of type 1 or type 7 on the Bristol Stool Scale, inflammatory bowel disease (IBD), history of rectovaginal fistula or cloacal defect, rectal prolapse, prior bowel diversion, fecal impaction, neurologic disorder leading to incontinence, use of loperamide or diphenoxylate within the last 30 days, childbirth within the last 3 months, need for antiretroviral drugs, hepatic impairment, or chronic abdominal pain without diarrhea. 

Baseline characteristics and symptoms severity were similar among participants. The average age of the women was 63 years, with 79% white and 85% postmenopausal. Participants had a mean (SD) of 1.6 (1.8) leaks per day. 

Participants were randomly assigned in a 0.5:1:1:1 fashion to receive oral placebo, loperamide, oral placebo with PFPT/biofeedback, or loperamide with PFPT/biofeedback. All participants received a standardized educational pamphlet that outlined dietary and behavioral recommendations. 

Women assigned to PFPT/biofeedback received 6 sessions every other week. Loperamide was started at a dosage of 2 mg per day with the possibility of dose maintenance, escalation, reduction, or discontinuation. 

Study outcomes. The primary outcome was a change from baseline to 24 weeks in the Vaizey FI symptom severity score, which assesses fecal frequency, urgency, and use of pads and medications. Secondary outcomes included assessment of a 7-day bowel diary and other quality-of-life measures. Data at 24 weeks were available for 89% of the women. 

All treatment groups experienced improved FI symptoms 

Based on changes in Vaizey scores after 24 weeks of treatment, women in all treatment groups had similar improvement in symptoms severity. However, those who received loperamide and PFPT/biofeedback had decreased pad changes per week and more accident-free days compared with women treated with placebo and biofeedback. Quality of life at 24 weeks was not statistically different between treatment groups as improvement was seen in all groups, including those who received oral placebo and patient education. 

Adverse events. The proportion of gastrointestinal adverse effects was similar between treatment groups, ranging from 45% to 63%. Constipation was the most common adverse event overall and was more common in those taking loperamide, occurring in 51% of the loperamide plus PFPT/biofeedback group, 38% of those who received loperamide alone, 23% of the biofeedback with placebo group, and 12% of the placebo-alone group. 

Strengths and limitations. Strengths of this study include its multisite, large sample size, low dropout rate, and sufficiently powered design to compare various combinations of first- and second-line therapies in women with a mean baseline FI of 1.6 leaks per day. Another strength is the robustness of the PFPT/biofeedback sessions that used anorectal manometry. This may, however, limit the study's external validity given that clinical use of this device is likely rare. Additionally, the population was comprised largely of postmenopausal and white women, which may make the findings less generalizable to other populations. 

Continue to: Novel vaginal bowel control system...

Novel vaginal bowel control system is effective, durable over 12 months for FI treatment 

Richter HE, Dunivan G, Brown HW, et al. A 12-month clinical durability of effectiveness and safety evaluation of a vaginal bowel control system for the nonsurgical treatment of fecal incontinence. Female Pelvic Med Reconstr Surg. 2019;25:113-119. 

Richter and colleagues characterized clinical success, effect on quality of life, and durability over 12 months of a novel vaginal bowel control device (Eclipse System; Pelvalon) for FI in a prospective cohort study. The device is a silicone-coated vaginal insert with a detachable pump and balloon that deflects the rectovaginal septum posteriorly, thus impeding the passage of stool in the rectum (FIGURE 2). 

Study eligibility criteria and treatment protocol 

Women were eligible for the study if they had 4 or more episodes of fecal soiling on a 2-week bowel diary and had FI for at least 6 months. Participants were excluded if they had prolapse outside the hymen, rectovaginal fistula, IBD, congenital anorectal malformation, urinary or colorectal infection, chronic pelvic or anorectal pain, pregnancy or planning pregnancy in the next 5 months, unmanaged chronic watery diarrhea, presence of an open wound or tear in the vagina, significant urogenital atrophy, or any psychiatric or neurologic disorder that would hinder the ability to participate. 

Participants successfully fitted with the device (3 attempts were allowed) were entered into the study's run-in phase. Those who were successfully fitted and had a 50% or greater reduction in FI continued into the treatment phase with 12 months of follow-up. 

Of the 137 women eligible for device fitting, 62% were successfully fitted. The 73 (86%) women who had a 50% or greater reduction in FI during the run-in period comprised the intent-to-treat study population. On average, these women were 61.3 years of age, with 70% white and 82% postmenopausal. At baseline, they had a mean of 14.1 episodes of FI over 2 weeks. (Prior to enrollment, 97.3% of women attempted self-management strategies, 17.8% to 23% failed conservative therapy, and 7.8% to 13.7% failed surgical therapy.) The follow-up rate at 12 months was 74%. 

Study outcomes. The primary outcome was treatment success, defined as proportion of subjects with a 50% or greater reduction in FI episodes at 3 months; this outcome also was evaluated at 6 and 12 months. Secondary outcomes were the number of FI episodes and quality-of-life measures at 3, 6, and 12 months. 

Treatment success, patient satisfaction high 

In the treatment phase, women had sustained improvements in symptom severity and quality-of-life measures over 12 months. Treatment success was 73% at 3 months, 71% at 6 months, and 70% at 12 months. Complete continence was achieved in 46% of participants at 12 months, and major FI episodes (requiring immediate change of undergarments) decreased from 5.0 at baseline to 0.5 at 12 months. Quality-of-life measures were improved at 3 months, and improvement was sustained over 12 months. Satisfaction was 94% at 12 months. 

Adverse events. No serious device-related adverse events occurred. Mild device-related adverse events were experienced by 45% of women during the fitting process and by 38% during treatment period. These included vaginal wall injury such as hyperemia and erosion; vaginal or pelvic discomfort; vaginal infection; constipation; and lower urinary tract issues such as urinary tract infection, urinary incontinence, and voiding dysfunction. No adverse events led to treatment discontinuation. 

Strengths and limitations. Strengths of this study include that it was conducted at multiple clinical sites, had a large sample size, and had a 1-year follow-up period in a population with daily FI. A limitation was that only women who had a 50% or greater reduction in FI episodes during the run-in period were followed for 12 months; however, this was 86% of the original cohort. The use of a comparative group using other devices, such as anal plugs, would have strengthened this study. 

Continue to: Sacroneuromodulation for FI…

Sacral neuromodulation for FI is effective long-term 

Hull T, Giese C, Wexner SD, et al; for the SNS Study Group. Long-term durability of sacral nerve stimulation therapy for chronic fecal incontinence. Dis Colon Rectum. 2013;56:234-245. 

In this multicenter, prospective cohort study, Hull and colleagues evaluated the 5-year efficacy of sacral neuromodulation (SNM), also known as sacral nerve stimulation, for treatment of FI. This study followed an earlier investigation by Wexner and colleagues, which reported that 83% of 120 patients treated with SNM had a 50% or greater improvement in FI episodes at 12 months.¹⁶ 

Details of the study 

The investigators enrolled 133 participants (92% female) who had more than 2 episodes of FI per week for longer than 6 months (12 months after vaginal delivery). Participants were excluded if they had congenital anorectal malformations, prior rectal surgery within the past 12 months (or 24 months if due to cancer), defects greater than 120° of the external anal sphincter (EAS), IBD, unmanaged chronic watery diarrhea, stool consistency type 6 or type 7 on the Bristol Stool Scale, sequela of pelvic radiation, active anal abscess or fistula, pregnancy, or planned pregnancy. 

Eligible participants underwent a 2-stage procedure with the InterStim bowel control device (Medtronic). If participants experienced a 50% or greater reduction in incontinence episodes with a wearable external SNM device in the test stimulation (stage 1), they received the chronic SNM implant device (stage 2). 

Participants who underwent device implantation were followed at 1, 3, and 6 months and annually for 5 years or until they exited the study. Bowel diaries and quality of life assessments were completed at baseline and at follow-up. 

The primary outcome was therapeutic success, defined as 50% or greater improvement in FI episodes per week. 

A total of 120 participants (90%) underwent implantation of the chronic lead and neuromodulator, and 76 (63%) were followed for 5 years. Baseline characteristics available in the initial study of 133 participants showed that the mean age was 60.5 years; 25% had undergone a prior anal sphincteroplasty; and 16.5% and 10.5% had EAS or internal anal sphincter (IAS) defects, respectively, on endoanal ultrasonography.¹⁶ 

Therapeutic success was high at 5 years 

At the 5-year follow-up, 89% (64/72) of participants met therapeutic success, with a reduction in weekly FI episodes from 9.1 at baseline to 1.7 at 5 years. The number of incontinence pads required decreased, and more participants wore no pads at 5 years. In the intention-to-treat analysis, carrying forward the baseline FI rate in participants who lacked follow-up data, the therapeutic success rate was 69%. Quality-of-life measures improved at 5 years, both statistically and by minimal clinical difference. 

Adverse events. Sixty-eight percent of participants experienced device-related adverse events, including implant site pain, change in sensation of stimulation, change in efficacy, implant site infection, or neurostimulator battery depletion (neurostimulator use commonly expires after 3 to 5 years). Of these events, 80% were successfully treated with medications, reprogramming, or no intervention. The 5-year probability of device revision or replacement was 24.4%, and the 5-year probability of device explant was 19.0%. 

Strengths and limitations. Overall, this study was a well-designed, multicenter trial with long-term follow-up that showed significant improvement in FI with the use of SNM. Its strengths include the enrollment of postmenopausal women who had current defects in EAS and/or IAS on endoanal ultrasonography and 25% who had a prior sphincteroplasty. The findings therefore are relevant to the gynecologic population in whom anal sphincteroplasty would not be recommended. The study also accounted for dropouts and reported the adjusted success rate of 69% at 5 years in that group. 

The lack of a control arm to rule out the placebo effect is a limitation of this study, although randomized trials comparing the effect of SNM "on" versus "off" showed greater improvement with the device "on."¹⁷ 

Fecal incontinence (FI), also known as accidental bowel leakage, is the involuntary loss of feces, which includes both liquid and solid stool as defined by the International Continence Society (ICS) and the International Urogynecological Association (IUGA).^1,2 Fecal incontinence is common, occurring in 7% to 25% of community-dwelling women, and it increases with age.^2-6 The condition is rarely addressed, with only 30% of women seeking care.^6-8 This is due to patient embarrassment and the lack of a reliable screening tool. However, FI affects quality of life and mental health, and the associated economic burden likely will rise given the increased prevalence of FI among older women.^2,4,7,9

Fecal incontinence occurs due to poor stool consistency, anal and pelvic muscle weakness, reduced rectal compliance, reduced or increased rectal sensation, or bowel inflammation or dysfunction. Many conditions can cause FI (TABLE 1).^5,10,11 It is therefore important to elicit a full medical history with a focus on specific bowel symptoms, such as stool consistency type (TABLE 2),¹² FI frequency, and duration of symptoms, as well as to perform a complete examination to identify any readily reversible or malignant causes. A colonoscopy is recommended for individuals who meet screening criteria or present with a change in bowel symptoms, such as diarrhea, bleeding, or obstruction.^13,14

Fecal incontinence treatments include a range of approaches categorized from conservative, or first-line therapy, to fourth-line surgical managements (FIGURE 1).^1,10,13,14 In this Update, we review the results of 3 well-designed trials that enrolled women with frequent nonneurogenic FI. 

Common first- and second-line treatments produce equivalent improvements in FI symptoms at
6 months 

Jelovsek JE, Markland AD, Whitehead WE, et al; National Institute of Child Health and Human Development Pelvic Floor Disorders Network. Controlling faecal incontinence in women by performing anal exercises with biofeedback or loperamide: a randomized clinical trial. Lancet Gastroenterol Hepatol. 2019;4:698-710. 

In a multicenter, randomized trial of first- and second-line treatments for FI, Jelovsek and colleagues evaluated the efficacy of oral placebo, loperamide, pelvic floor physical therapy (PFPT) with biofeedback using anorectal manometry, or combination therapy over a 24-week period. 

Continue to: Four treatments compared...

Three hundred women with FI occurring monthly for 3 months were included in the trial. Women were excluded if they had a stool classification of type 1 or type 7 on the Bristol Stool Scale, inflammatory bowel disease (IBD), history of rectovaginal fistula or cloacal defect, rectal prolapse, prior bowel diversion, fecal impaction, neurologic disorder leading to incontinence, use of loperamide or diphenoxylate within the last 30 days, childbirth within the last 3 months, need for antiretroviral drugs, hepatic impairment, or chronic abdominal pain without diarrhea. 

Baseline characteristics and symptoms severity were similar among participants. The average age of the women was 63 years, with 79% white and 85% postmenopausal. Participants had a mean (SD) of 1.6 (1.8) leaks per day. 

Participants were randomly assigned in a 0.5:1:1:1 fashion to receive oral placebo, loperamide, oral placebo with PFPT/biofeedback, or loperamide with PFPT/biofeedback. All participants received a standardized educational pamphlet that outlined dietary and behavioral recommendations. 

Women assigned to PFPT/biofeedback received 6 sessions every other week. Loperamide was started at a dosage of 2 mg per day with the possibility of dose maintenance, escalation, reduction, or discontinuation. 

Study outcomes. The primary outcome was a change from baseline to 24 weeks in the Vaizey FI symptom severity score, which assesses fecal frequency, urgency, and use of pads and medications. Secondary outcomes included assessment of a 7-day bowel diary and other quality-of-life measures. Data at 24 weeks were available for 89% of the women. 

All treatment groups experienced improved FI symptoms 

Based on changes in Vaizey scores after 24 weeks of treatment, women in all treatment groups had similar improvement in symptoms severity. However, those who received loperamide and PFPT/biofeedback had decreased pad changes per week and more accident-free days compared with women treated with placebo and biofeedback. Quality of life at 24 weeks was not statistically different between treatment groups as improvement was seen in all groups, including those who received oral placebo and patient education. 

Adverse events. The proportion of gastrointestinal adverse effects was similar between treatment groups, ranging from 45% to 63%. Constipation was the most common adverse event overall and was more common in those taking loperamide, occurring in 51% of the loperamide plus PFPT/biofeedback group, 38% of those who received loperamide alone, 23% of the biofeedback with placebo group, and 12% of the placebo-alone group. 

Strengths and limitations. Strengths of this study include its multisite, large sample size, low dropout rate, and sufficiently powered design to compare various combinations of first- and second-line therapies in women with a mean baseline FI of 1.6 leaks per day. Another strength is the robustness of the PFPT/biofeedback sessions that used anorectal manometry. This may, however, limit the study's external validity given that clinical use of this device is likely rare. Additionally, the population was comprised largely of postmenopausal and white women, which may make the findings less generalizable to other populations. 

Continue to: Novel vaginal bowel control system...

Novel vaginal bowel control system is effective, durable over 12 months for FI treatment 

Richter HE, Dunivan G, Brown HW, et al. A 12-month clinical durability of effectiveness and safety evaluation of a vaginal bowel control system for the nonsurgical treatment of fecal incontinence. Female Pelvic Med Reconstr Surg. 2019;25:113-119. 

Richter and colleagues characterized clinical success, effect on quality of life, and durability over 12 months of a novel vaginal bowel control device (Eclipse System; Pelvalon) for FI in a prospective cohort study. The device is a silicone-coated vaginal insert with a detachable pump and balloon that deflects the rectovaginal septum posteriorly, thus impeding the passage of stool in the rectum (FIGURE 2). 

Study eligibility criteria and treatment protocol 

Women were eligible for the study if they had 4 or more episodes of fecal soiling on a 2-week bowel diary and had FI for at least 6 months. Participants were excluded if they had prolapse outside the hymen, rectovaginal fistula, IBD, congenital anorectal malformation, urinary or colorectal infection, chronic pelvic or anorectal pain, pregnancy or planning pregnancy in the next 5 months, unmanaged chronic watery diarrhea, presence of an open wound or tear in the vagina, significant urogenital atrophy, or any psychiatric or neurologic disorder that would hinder the ability to participate. 

Participants successfully fitted with the device (3 attempts were allowed) were entered into the study's run-in phase. Those who were successfully fitted and had a 50% or greater reduction in FI continued into the treatment phase with 12 months of follow-up. 

Of the 137 women eligible for device fitting, 62% were successfully fitted. The 73 (86%) women who had a 50% or greater reduction in FI during the run-in period comprised the intent-to-treat study population. On average, these women were 61.3 years of age, with 70% white and 82% postmenopausal. At baseline, they had a mean of 14.1 episodes of FI over 2 weeks. (Prior to enrollment, 97.3% of women attempted self-management strategies, 17.8% to 23% failed conservative therapy, and 7.8% to 13.7% failed surgical therapy.) The follow-up rate at 12 months was 74%. 

Study outcomes. The primary outcome was treatment success, defined as proportion of subjects with a 50% or greater reduction in FI episodes at 3 months; this outcome also was evaluated at 6 and 12 months. Secondary outcomes were the number of FI episodes and quality-of-life measures at 3, 6, and 12 months. 

Treatment success, patient satisfaction high 

In the treatment phase, women had sustained improvements in symptom severity and quality-of-life measures over 12 months. Treatment success was 73% at 3 months, 71% at 6 months, and 70% at 12 months. Complete continence was achieved in 46% of participants at 12 months, and major FI episodes (requiring immediate change of undergarments) decreased from 5.0 at baseline to 0.5 at 12 months. Quality-of-life measures were improved at 3 months, and improvement was sustained over 12 months. Satisfaction was 94% at 12 months. 

Adverse events. No serious device-related adverse events occurred. Mild device-related adverse events were experienced by 45% of women during the fitting process and by 38% during treatment period. These included vaginal wall injury such as hyperemia and erosion; vaginal or pelvic discomfort; vaginal infection; constipation; and lower urinary tract issues such as urinary tract infection, urinary incontinence, and voiding dysfunction. No adverse events led to treatment discontinuation. 

Strengths and limitations. Strengths of this study include that it was conducted at multiple clinical sites, had a large sample size, and had a 1-year follow-up period in a population with daily FI. A limitation was that only women who had a 50% or greater reduction in FI episodes during the run-in period were followed for 12 months; however, this was 86% of the original cohort. The use of a comparative group using other devices, such as anal plugs, would have strengthened this study. 

Continue to: Sacroneuromodulation for FI…

Sacral neuromodulation for FI is effective long-term 

Hull T, Giese C, Wexner SD, et al; for the SNS Study Group. Long-term durability of sacral nerve stimulation therapy for chronic fecal incontinence. Dis Colon Rectum. 2013;56:234-245. 

In this multicenter, prospective cohort study, Hull and colleagues evaluated the 5-year efficacy of sacral neuromodulation (SNM), also known as sacral nerve stimulation, for treatment of FI. This study followed an earlier investigation by Wexner and colleagues, which reported that 83% of 120 patients treated with SNM had a 50% or greater improvement in FI episodes at 12 months.¹⁶ 

Details of the study 

The investigators enrolled 133 participants (92% female) who had more than 2 episodes of FI per week for longer than 6 months (12 months after vaginal delivery). Participants were excluded if they had congenital anorectal malformations, prior rectal surgery within the past 12 months (or 24 months if due to cancer), defects greater than 120° of the external anal sphincter (EAS), IBD, unmanaged chronic watery diarrhea, stool consistency type 6 or type 7 on the Bristol Stool Scale, sequela of pelvic radiation, active anal abscess or fistula, pregnancy, or planned pregnancy. 

Eligible participants underwent a 2-stage procedure with the InterStim bowel control device (Medtronic). If participants experienced a 50% or greater reduction in incontinence episodes with a wearable external SNM device in the test stimulation (stage 1), they received the chronic SNM implant device (stage 2). 

Participants who underwent device implantation were followed at 1, 3, and 6 months and annually for 5 years or until they exited the study. Bowel diaries and quality of life assessments were completed at baseline and at follow-up. 

The primary outcome was therapeutic success, defined as 50% or greater improvement in FI episodes per week. 

A total of 120 participants (90%) underwent implantation of the chronic lead and neuromodulator, and 76 (63%) were followed for 5 years. Baseline characteristics available in the initial study of 133 participants showed that the mean age was 60.5 years; 25% had undergone a prior anal sphincteroplasty; and 16.5% and 10.5% had EAS or internal anal sphincter (IAS) defects, respectively, on endoanal ultrasonography.¹⁶ 

Therapeutic success was high at 5 years 

At the 5-year follow-up, 89% (64/72) of participants met therapeutic success, with a reduction in weekly FI episodes from 9.1 at baseline to 1.7 at 5 years. The number of incontinence pads required decreased, and more participants wore no pads at 5 years. In the intention-to-treat analysis, carrying forward the baseline FI rate in participants who lacked follow-up data, the therapeutic success rate was 69%. Quality-of-life measures improved at 5 years, both statistically and by minimal clinical difference. 

Adverse events. Sixty-eight percent of participants experienced device-related adverse events, including implant site pain, change in sensation of stimulation, change in efficacy, implant site infection, or neurostimulator battery depletion (neurostimulator use commonly expires after 3 to 5 years). Of these events, 80% were successfully treated with medications, reprogramming, or no intervention. The 5-year probability of device revision or replacement was 24.4%, and the 5-year probability of device explant was 19.0%. 

Strengths and limitations. Overall, this study was a well-designed, multicenter trial with long-term follow-up that showed significant improvement in FI with the use of SNM. Its strengths include the enrollment of postmenopausal women who had current defects in EAS and/or IAS on endoanal ultrasonography and 25% who had a prior sphincteroplasty. The findings therefore are relevant to the gynecologic population in whom anal sphincteroplasty would not be recommended. The study also accounted for dropouts and reported the adjusted success rate of 69% at 5 years in that group. 

The lack of a control arm to rule out the placebo effect is a limitation of this study, although randomized trials comparing the effect of SNM "on" versus "off" showed greater improvement with the device "on."¹⁷ 

“Take pride in your surgical work. Do it in such a way that you would be willing to sign your name to it…the operation was performed by me.”

—Raymond A. Lee, MD

The US Food and Drug Administration (FDA) recently ordered companies to cease selling transvaginal mesh intended for pelvic organ prolapse (POP) repair (but not for the treatment of stress urinary incontinence [SUI] or for abdominal sacrocolpopexy).^1,2 The FDA is also requiring companies preparing premarket approval applications for mesh products for the treatment of transvaginal POP to continue safety and efficacy follow-up in existing section 522 postmarket surveillance studies.³

It is, therefore, incumbent upon gynecologic surgeons to understand the surgical options that remain and perfect their surgical approach to POP to optimize patient outcomes. POP may be performed transvaginally or transabdominally, with each approach offering its own set of risks and benefits. The ability to perform both effectively allows the surgeon to tailor the approach to the condition and circumstances encountered. It is also important to realize that “cures” are elusive in POP surgery. While we can frequently alleviate patient symptoms and improve quality of life, a lifelong “cure” is an unrealistic goal for most prolapse procedures.

This article focuses on transvaginal native tissue repair,⁴ specifically the Mayo approach.

View related videos from Dr. Gebhart on apical suspension, anterior repair, and posterior repair techniques.

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Watch video here

Vaginal surgery fundamentals

Before we explore the details of the Mayo technique, let’s review some basic principles of vaginal surgery. First, it is important to make a good clinical diagnosis so that you know which compartments (apex, anterior, or posterior) are involved. Although single compartment defects exist, multicompartment defects are far more common. Failing to recognize all compartment defects often results in incomplete repair, which can mean recurrent prolapse and additional interventions.

Second, exposure is critical when performing surgery by any route. You must be able to see your surgical field completely in order to properly execute your surgical approach. Table height, lighting, and retraction are all important to surgical success.

Lastly, it is important to know how to effectively execute your intended procedure. Native tissue repair is often criticized for having a high failure rate. It makes sense that mesh augmentation offers greater durability of a repair, but an effective native tissue repair will also effectively treat the majority of patients. An ineffective repair does not benefit the patient and contributes to high failure rates.

Vaginal apex repairs

Data from the OPTIMAL trial suggest that uterosacral ligament suspension and sacrospinous ligament fixation are equally effective in treating apical prolapse.⁵ Our preference is a McCall culdoplasty (uterosacral ligament plication). It allows direct visualization (internally or externally) to place apical support stitches and plicates the ligaments in the midline of the vaginal cuff to help prevent enterocele protrusion. DeLancey has described the levels of support in the female pelvis and places importance on apical support.⁶ Keep in mind that anterior and posterior compartment prolapse is often accompanied by apical prolapse. Therefore, treating the apex is critical for overall success.

External vs internal McCall sutures: My technique. Envision the open vaginal cuff after completing a vaginal hysterectomy or after opening the vaginal cuff for a posthysterectomy vaginal vault prolapse (FIGURE 1). External (suture placed through the vaginal cuff epithelium into the peritoneal cavity, incorporating the uterosacral ligaments and intervening peritoneum, and ultimately brought back out through the posterior cuff and tied) or internal (suture placed in the intraperitoneal space, incorporating the uterosacral ligaments and intervening peritoneum, and tied internally) McCall sutures can be utilized (FIGURE 2). I prefer a combination of both. I use 0-polyglactin for external sutures, as the sutures will ultimately dissolve and not remain in the vaginal cavity. I usually place at least 2 external sutures with the lowest suture on the vaginal cuff being the deepest uterosacral stitch. Each subsequent suture is placed closer to the vaginal cuff and closer to the ends of the ligamentous stumps, starting deepest and working back toward the cuff with each stitch. I place 1 or 2 internal sutures (delayed absorbable or permanent) between my 2 external sutures. Because these sutures will be tied internally and located in the intraperitoneal space, permanent sutures may be used.

Continue to: Anterior compartment repairs...

Anterior compartment repairs

The anterior compartment seems the most susceptible to forces within the pelvis and is a common site of prolapse. Many theories exist as to what causes a cystocele—distension, displacement, detachment, etc. While paravaginal defects exist, I believe that most cystoceles arise horizontally at the base of the bladder as the anterior endopelvic fascia detaches from the apex or cervix. The tissue then attenuates as the hernia progresses.

For surgical success: Make certain your repair addresses re-establishing continuity of the anterior endopelvic fascia with the fascia and ligaments at the vaginal apex; it will increase your success in treating anterior compartment prolapse.

We prefer to mobilize the epithelium in the midline from the vaginal apex to the mid‑urethra (if performing a midurethral sling, we stop short of the bladder neck and perform a separate suburethral incision). When incising the epithelium in the midline, the underlying fascia is also split in the midline, creating a midline defect. Once the epithelium is split and mobilized laterally off the underlying fascia, we can begin reconstruction.

The midline fascial defect that was just created is closed with a running 2-0 polyglactin from just beneath the bladder neck down to and including the fascia and uterosacral ligaments at the apex. This is accomplished in an upside down ‘T’ orientation (FIGURE 3). It is critical that the fascia is reunited at the base or you will leave the patient with a hernia.

For surgical success: To check intraoperatively that the fascia is reunited at the base, try to place an index finger between the base of the cystocele repair and the apex. If you can insert your finger, that is where the hernia still exists. If you meet resistance with your finger, you are palpating reunification of the anterior and apical fascia.

Lastly, given that we have just dissected and then plicated the tissues beneath the bladder, I like to perform cystoscopy to be certain the bladder has not been violated. It is also important not to over-plicate the anterior fascia so that the sutures shear through the fascia and weaken the support or narrow the vaginal lumen.

Continue to: Posterior compartment repairs...

Posterior compartment repairs

Like with the anterior compartment, opinions differ as to the site of posterior compartment prolapse. Midline, lateral, distal, and site-specific defects and surgical approaches have been described. Research suggests that there is no benefit to the use of mesh in the posterior compartment.⁷ It is very important to recognize that over-plication of the posterior compartment can lead to narrowing/stricture and dyspareunia. Therefore, monitor vaginal caliber throughout repair of the posterior compartment.

Although we believe that a midline defect in the endopelvic fascia is primarily responsible for rectoceles, we also appreciate that the fascia must be reconstructed all the way to the perineal body and that narrowing the genital hiatus is very important and often underappreciated (FIGURE 5). Thus, perineal reconstruction is universally performed. I will emphasize again that reconstruction must be performed while also monitoring vaginal caliber. If it is too tight with the patient under anesthesia, it will be too tight when the patient recovers. Avoidance is the best option. If the patient does not desire a functional vagina (eg, an elderly patient), then narrowing is a desired goal.

Perineal reconstruction technique and tips for success

A retractor at 12 o’clock to support the apex and anterior wall can be helpful for visualization in the posterior compartment. We start with a v-shaped incision on the perineum. The width is determined by how much you want to build up the perineum and narrow the vagina (the wider the incision, the more building up of the perineal body and vaginal narrowing). A strip of epithelium is then mobilized in the midline (be careful not to excise too much). This dissection is carried all the way up the midline to just short of the tied apical suspension sutures at the posterior vaginal apex. The posterior dissection tends to be the most vascular in my experience.

Utilize cautery to obtain hemostasis along your dissection margins while protecting the underlying rectum. We have not found it necessary to dissect the posterior epithelium off the underlying fascia (that is an option at this point, however, if you feel more comfortable doing this). With an index finger in the vagina, compressing the rectum posteriorly, interrupted 1-0 polyglactin suture is placed through the epithelium and underlying fascia (avoiding the rectum) on one side, then the other, and then tied. The next sutures are placed utilizing the same technique, and the caliber of the vagina is noted with the placement of each suture (if it is too tight, then remove and replace the suture and recheck). It is important to realize you want to plicate the fascia in the midline and not perform an aggressive levatorplasty that could lead to muscle pain. Additionally, each suture should get the same purchase of tissue on each side, and the spacing of each suture should be uniform, like rungs on a ladder. Ultimately, the repair is carried down to the hymenal ring. At this point, the perineal reconstruction is performed, plicating the perineal body in the midline with deeper horizontal sutures and then closing the perineal skin with interrupted or subcuticular sutures (FIGURE 6). Completion of these repairs should orient the vagina toward the hollow of the sacrum (FIGURE 7), allowing downward forces to compress the vaginal supports posteriorly onto the pelvic floor instead of forcing it out the vaginal lumen (FIGURE 8).

Our patients generally stay in the hospital overnight, and we place a vaginal pack to provide topical pressure throughout the vagina overnight. We tell patients no lifting more than 15 lb and no intercourse for 6 weeks. While we do not tend to use hydrodissection in our repairs, it is a perfectly acceptable option.

Continue to: Commit to knowledge of native tissue techniques...

Commit to knowledge of native tissue techniques

Given the recent FDA ban on the sale of transvaginal mesh for POP and the public’s negative perception of mesh (based often on misleading information in the media), it is incumbent upon gynecologic surgeons to invest in learning or relearning effective native tissue techniques for the transvaginal treatment of POP. While not perfect, they offer an effective nonmesh treatment option for many of our patients.

“Take pride in your surgical work. Do it in such a way that you would be willing to sign your name to it…the operation was performed by me.”

—Raymond A. Lee, MD

The US Food and Drug Administration (FDA) recently ordered companies to cease selling transvaginal mesh intended for pelvic organ prolapse (POP) repair (but not for the treatment of stress urinary incontinence [SUI] or for abdominal sacrocolpopexy).^1,2 The FDA is also requiring companies preparing premarket approval applications for mesh products for the treatment of transvaginal POP to continue safety and efficacy follow-up in existing section 522 postmarket surveillance studies.³

It is, therefore, incumbent upon gynecologic surgeons to understand the surgical options that remain and perfect their surgical approach to POP to optimize patient outcomes. POP may be performed transvaginally or transabdominally, with each approach offering its own set of risks and benefits. The ability to perform both effectively allows the surgeon to tailor the approach to the condition and circumstances encountered. It is also important to realize that “cures” are elusive in POP surgery. While we can frequently alleviate patient symptoms and improve quality of life, a lifelong “cure” is an unrealistic goal for most prolapse procedures.

This article focuses on transvaginal native tissue repair,⁴ specifically the Mayo approach.

View related videos from Dr. Gebhart on apical suspension, anterior repair, and posterior repair techniques.

---

Watch video here

Vaginal surgery fundamentals

Before we explore the details of the Mayo technique, let’s review some basic principles of vaginal surgery. First, it is important to make a good clinical diagnosis so that you know which compartments (apex, anterior, or posterior) are involved. Although single compartment defects exist, multicompartment defects are far more common. Failing to recognize all compartment defects often results in incomplete repair, which can mean recurrent prolapse and additional interventions.

Second, exposure is critical when performing surgery by any route. You must be able to see your surgical field completely in order to properly execute your surgical approach. Table height, lighting, and retraction are all important to surgical success.

Lastly, it is important to know how to effectively execute your intended procedure. Native tissue repair is often criticized for having a high failure rate. It makes sense that mesh augmentation offers greater durability of a repair, but an effective native tissue repair will also effectively treat the majority of patients. An ineffective repair does not benefit the patient and contributes to high failure rates.

Vaginal apex repairs

Data from the OPTIMAL trial suggest that uterosacral ligament suspension and sacrospinous ligament fixation are equally effective in treating apical prolapse.⁵ Our preference is a McCall culdoplasty (uterosacral ligament plication). It allows direct visualization (internally or externally) to place apical support stitches and plicates the ligaments in the midline of the vaginal cuff to help prevent enterocele protrusion. DeLancey has described the levels of support in the female pelvis and places importance on apical support.⁶ Keep in mind that anterior and posterior compartment prolapse is often accompanied by apical prolapse. Therefore, treating the apex is critical for overall success.

External vs internal McCall sutures: My technique. Envision the open vaginal cuff after completing a vaginal hysterectomy or after opening the vaginal cuff for a posthysterectomy vaginal vault prolapse (FIGURE 1). External (suture placed through the vaginal cuff epithelium into the peritoneal cavity, incorporating the uterosacral ligaments and intervening peritoneum, and ultimately brought back out through the posterior cuff and tied) or internal (suture placed in the intraperitoneal space, incorporating the uterosacral ligaments and intervening peritoneum, and tied internally) McCall sutures can be utilized (FIGURE 2). I prefer a combination of both. I use 0-polyglactin for external sutures, as the sutures will ultimately dissolve and not remain in the vaginal cavity. I usually place at least 2 external sutures with the lowest suture on the vaginal cuff being the deepest uterosacral stitch. Each subsequent suture is placed closer to the vaginal cuff and closer to the ends of the ligamentous stumps, starting deepest and working back toward the cuff with each stitch. I place 1 or 2 internal sutures (delayed absorbable or permanent) between my 2 external sutures. Because these sutures will be tied internally and located in the intraperitoneal space, permanent sutures may be used.

Continue to: Anterior compartment repairs...

Anterior compartment repairs

The anterior compartment seems the most susceptible to forces within the pelvis and is a common site of prolapse. Many theories exist as to what causes a cystocele—distension, displacement, detachment, etc. While paravaginal defects exist, I believe that most cystoceles arise horizontally at the base of the bladder as the anterior endopelvic fascia detaches from the apex or cervix. The tissue then attenuates as the hernia progresses.

For surgical success: Make certain your repair addresses re-establishing continuity of the anterior endopelvic fascia with the fascia and ligaments at the vaginal apex; it will increase your success in treating anterior compartment prolapse.

We prefer to mobilize the epithelium in the midline from the vaginal apex to the mid‑urethra (if performing a midurethral sling, we stop short of the bladder neck and perform a separate suburethral incision). When incising the epithelium in the midline, the underlying fascia is also split in the midline, creating a midline defect. Once the epithelium is split and mobilized laterally off the underlying fascia, we can begin reconstruction.

The midline fascial defect that was just created is closed with a running 2-0 polyglactin from just beneath the bladder neck down to and including the fascia and uterosacral ligaments at the apex. This is accomplished in an upside down ‘T’ orientation (FIGURE 3). It is critical that the fascia is reunited at the base or you will leave the patient with a hernia.

For surgical success: To check intraoperatively that the fascia is reunited at the base, try to place an index finger between the base of the cystocele repair and the apex. If you can insert your finger, that is where the hernia still exists. If you meet resistance with your finger, you are palpating reunification of the anterior and apical fascia.

Lastly, given that we have just dissected and then plicated the tissues beneath the bladder, I like to perform cystoscopy to be certain the bladder has not been violated. It is also important not to over-plicate the anterior fascia so that the sutures shear through the fascia and weaken the support or narrow the vaginal lumen.

Continue to: Posterior compartment repairs...

Posterior compartment repairs

Like with the anterior compartment, opinions differ as to the site of posterior compartment prolapse. Midline, lateral, distal, and site-specific defects and surgical approaches have been described. Research suggests that there is no benefit to the use of mesh in the posterior compartment.⁷ It is very important to recognize that over-plication of the posterior compartment can lead to narrowing/stricture and dyspareunia. Therefore, monitor vaginal caliber throughout repair of the posterior compartment.

Although we believe that a midline defect in the endopelvic fascia is primarily responsible for rectoceles, we also appreciate that the fascia must be reconstructed all the way to the perineal body and that narrowing the genital hiatus is very important and often underappreciated (FIGURE 5). Thus, perineal reconstruction is universally performed. I will emphasize again that reconstruction must be performed while also monitoring vaginal caliber. If it is too tight with the patient under anesthesia, it will be too tight when the patient recovers. Avoidance is the best option. If the patient does not desire a functional vagina (eg, an elderly patient), then narrowing is a desired goal.

Perineal reconstruction technique and tips for success

A retractor at 12 o’clock to support the apex and anterior wall can be helpful for visualization in the posterior compartment. We start with a v-shaped incision on the perineum. The width is determined by how much you want to build up the perineum and narrow the vagina (the wider the incision, the more building up of the perineal body and vaginal narrowing). A strip of epithelium is then mobilized in the midline (be careful not to excise too much). This dissection is carried all the way up the midline to just short of the tied apical suspension sutures at the posterior vaginal apex. The posterior dissection tends to be the most vascular in my experience.

Utilize cautery to obtain hemostasis along your dissection margins while protecting the underlying rectum. We have not found it necessary to dissect the posterior epithelium off the underlying fascia (that is an option at this point, however, if you feel more comfortable doing this). With an index finger in the vagina, compressing the rectum posteriorly, interrupted 1-0 polyglactin suture is placed through the epithelium and underlying fascia (avoiding the rectum) on one side, then the other, and then tied. The next sutures are placed utilizing the same technique, and the caliber of the vagina is noted with the placement of each suture (if it is too tight, then remove and replace the suture and recheck). It is important to realize you want to plicate the fascia in the midline and not perform an aggressive levatorplasty that could lead to muscle pain. Additionally, each suture should get the same purchase of tissue on each side, and the spacing of each suture should be uniform, like rungs on a ladder. Ultimately, the repair is carried down to the hymenal ring. At this point, the perineal reconstruction is performed, plicating the perineal body in the midline with deeper horizontal sutures and then closing the perineal skin with interrupted or subcuticular sutures (FIGURE 6). Completion of these repairs should orient the vagina toward the hollow of the sacrum (FIGURE 7), allowing downward forces to compress the vaginal supports posteriorly onto the pelvic floor instead of forcing it out the vaginal lumen (FIGURE 8).

Our patients generally stay in the hospital overnight, and we place a vaginal pack to provide topical pressure throughout the vagina overnight. We tell patients no lifting more than 15 lb and no intercourse for 6 weeks. While we do not tend to use hydrodissection in our repairs, it is a perfectly acceptable option.

Continue to: Commit to knowledge of native tissue techniques...

Commit to knowledge of native tissue techniques

Given the recent FDA ban on the sale of transvaginal mesh for POP and the public’s negative perception of mesh (based often on misleading information in the media), it is incumbent upon gynecologic surgeons to invest in learning or relearning effective native tissue techniques for the transvaginal treatment of POP. While not perfect, they offer an effective nonmesh treatment option for many of our patients.

“Take pride in your surgical work. Do it in such a way that you would be willing to sign your name to it…the operation was performed by me.”

—Raymond A. Lee, MD

The US Food and Drug Administration (FDA) recently ordered companies to cease selling transvaginal mesh intended for pelvic organ prolapse (POP) repair (but not for the treatment of stress urinary incontinence [SUI] or for abdominal sacrocolpopexy).^1,2 The FDA is also requiring companies preparing premarket approval applications for mesh products for the treatment of transvaginal POP to continue safety and efficacy follow-up in existing section 522 postmarket surveillance studies.³

It is, therefore, incumbent upon gynecologic surgeons to understand the surgical options that remain and perfect their surgical approach to POP to optimize patient outcomes. POP may be performed transvaginally or transabdominally, with each approach offering its own set of risks and benefits. The ability to perform both effectively allows the surgeon to tailor the approach to the condition and circumstances encountered. It is also important to realize that “cures” are elusive in POP surgery. While we can frequently alleviate patient symptoms and improve quality of life, a lifelong “cure” is an unrealistic goal for most prolapse procedures.

This article focuses on transvaginal native tissue repair,⁴ specifically the Mayo approach.

View related videos from Dr. Gebhart on apical suspension, anterior repair, and posterior repair techniques.

---

Watch video here

Vaginal surgery fundamentals

Before we explore the details of the Mayo technique, let’s review some basic principles of vaginal surgery. First, it is important to make a good clinical diagnosis so that you know which compartments (apex, anterior, or posterior) are involved. Although single compartment defects exist, multicompartment defects are far more common. Failing to recognize all compartment defects often results in incomplete repair, which can mean recurrent prolapse and additional interventions.

Second, exposure is critical when performing surgery by any route. You must be able to see your surgical field completely in order to properly execute your surgical approach. Table height, lighting, and retraction are all important to surgical success.

Lastly, it is important to know how to effectively execute your intended procedure. Native tissue repair is often criticized for having a high failure rate. It makes sense that mesh augmentation offers greater durability of a repair, but an effective native tissue repair will also effectively treat the majority of patients. An ineffective repair does not benefit the patient and contributes to high failure rates.

Vaginal apex repairs

Data from the OPTIMAL trial suggest that uterosacral ligament suspension and sacrospinous ligament fixation are equally effective in treating apical prolapse.⁵ Our preference is a McCall culdoplasty (uterosacral ligament plication). It allows direct visualization (internally or externally) to place apical support stitches and plicates the ligaments in the midline of the vaginal cuff to help prevent enterocele protrusion. DeLancey has described the levels of support in the female pelvis and places importance on apical support.⁶ Keep in mind that anterior and posterior compartment prolapse is often accompanied by apical prolapse. Therefore, treating the apex is critical for overall success.

External vs internal McCall sutures: My technique. Envision the open vaginal cuff after completing a vaginal hysterectomy or after opening the vaginal cuff for a posthysterectomy vaginal vault prolapse (FIGURE 1). External (suture placed through the vaginal cuff epithelium into the peritoneal cavity, incorporating the uterosacral ligaments and intervening peritoneum, and ultimately brought back out through the posterior cuff and tied) or internal (suture placed in the intraperitoneal space, incorporating the uterosacral ligaments and intervening peritoneum, and tied internally) McCall sutures can be utilized (FIGURE 2). I prefer a combination of both. I use 0-polyglactin for external sutures, as the sutures will ultimately dissolve and not remain in the vaginal cavity. I usually place at least 2 external sutures with the lowest suture on the vaginal cuff being the deepest uterosacral stitch. Each subsequent suture is placed closer to the vaginal cuff and closer to the ends of the ligamentous stumps, starting deepest and working back toward the cuff with each stitch. I place 1 or 2 internal sutures (delayed absorbable or permanent) between my 2 external sutures. Because these sutures will be tied internally and located in the intraperitoneal space, permanent sutures may be used.

Continue to: Anterior compartment repairs...

Anterior compartment repairs

The anterior compartment seems the most susceptible to forces within the pelvis and is a common site of prolapse. Many theories exist as to what causes a cystocele—distension, displacement, detachment, etc. While paravaginal defects exist, I believe that most cystoceles arise horizontally at the base of the bladder as the anterior endopelvic fascia detaches from the apex or cervix. The tissue then attenuates as the hernia progresses.

For surgical success: Make certain your repair addresses re-establishing continuity of the anterior endopelvic fascia with the fascia and ligaments at the vaginal apex; it will increase your success in treating anterior compartment prolapse.

We prefer to mobilize the epithelium in the midline from the vaginal apex to the mid‑urethra (if performing a midurethral sling, we stop short of the bladder neck and perform a separate suburethral incision). When incising the epithelium in the midline, the underlying fascia is also split in the midline, creating a midline defect. Once the epithelium is split and mobilized laterally off the underlying fascia, we can begin reconstruction.

The midline fascial defect that was just created is closed with a running 2-0 polyglactin from just beneath the bladder neck down to and including the fascia and uterosacral ligaments at the apex. This is accomplished in an upside down ‘T’ orientation (FIGURE 3). It is critical that the fascia is reunited at the base or you will leave the patient with a hernia.

For surgical success: To check intraoperatively that the fascia is reunited at the base, try to place an index finger between the base of the cystocele repair and the apex. If you can insert your finger, that is where the hernia still exists. If you meet resistance with your finger, you are palpating reunification of the anterior and apical fascia.

Lastly, given that we have just dissected and then plicated the tissues beneath the bladder, I like to perform cystoscopy to be certain the bladder has not been violated. It is also important not to over-plicate the anterior fascia so that the sutures shear through the fascia and weaken the support or narrow the vaginal lumen.

Continue to: Posterior compartment repairs...

Posterior compartment repairs

Like with the anterior compartment, opinions differ as to the site of posterior compartment prolapse. Midline, lateral, distal, and site-specific defects and surgical approaches have been described. Research suggests that there is no benefit to the use of mesh in the posterior compartment.⁷ It is very important to recognize that over-plication of the posterior compartment can lead to narrowing/stricture and dyspareunia. Therefore, monitor vaginal caliber throughout repair of the posterior compartment.

Although we believe that a midline defect in the endopelvic fascia is primarily responsible for rectoceles, we also appreciate that the fascia must be reconstructed all the way to the perineal body and that narrowing the genital hiatus is very important and often underappreciated (FIGURE 5). Thus, perineal reconstruction is universally performed. I will emphasize again that reconstruction must be performed while also monitoring vaginal caliber. If it is too tight with the patient under anesthesia, it will be too tight when the patient recovers. Avoidance is the best option. If the patient does not desire a functional vagina (eg, an elderly patient), then narrowing is a desired goal.

Perineal reconstruction technique and tips for success

A retractor at 12 o’clock to support the apex and anterior wall can be helpful for visualization in the posterior compartment. We start with a v-shaped incision on the perineum. The width is determined by how much you want to build up the perineum and narrow the vagina (the wider the incision, the more building up of the perineal body and vaginal narrowing). A strip of epithelium is then mobilized in the midline (be careful not to excise too much). This dissection is carried all the way up the midline to just short of the tied apical suspension sutures at the posterior vaginal apex. The posterior dissection tends to be the most vascular in my experience.

Utilize cautery to obtain hemostasis along your dissection margins while protecting the underlying rectum. We have not found it necessary to dissect the posterior epithelium off the underlying fascia (that is an option at this point, however, if you feel more comfortable doing this). With an index finger in the vagina, compressing the rectum posteriorly, interrupted 1-0 polyglactin suture is placed through the epithelium and underlying fascia (avoiding the rectum) on one side, then the other, and then tied. The next sutures are placed utilizing the same technique, and the caliber of the vagina is noted with the placement of each suture (if it is too tight, then remove and replace the suture and recheck). It is important to realize you want to plicate the fascia in the midline and not perform an aggressive levatorplasty that could lead to muscle pain. Additionally, each suture should get the same purchase of tissue on each side, and the spacing of each suture should be uniform, like rungs on a ladder. Ultimately, the repair is carried down to the hymenal ring. At this point, the perineal reconstruction is performed, plicating the perineal body in the midline with deeper horizontal sutures and then closing the perineal skin with interrupted or subcuticular sutures (FIGURE 6). Completion of these repairs should orient the vagina toward the hollow of the sacrum (FIGURE 7), allowing downward forces to compress the vaginal supports posteriorly onto the pelvic floor instead of forcing it out the vaginal lumen (FIGURE 8).

Our patients generally stay in the hospital overnight, and we place a vaginal pack to provide topical pressure throughout the vagina overnight. We tell patients no lifting more than 15 lb and no intercourse for 6 weeks. While we do not tend to use hydrodissection in our repairs, it is a perfectly acceptable option.

Continue to: Commit to knowledge of native tissue techniques...

Commit to knowledge of native tissue techniques

Given the recent FDA ban on the sale of transvaginal mesh for POP and the public’s negative perception of mesh (based often on misleading information in the media), it is incumbent upon gynecologic surgeons to invest in learning or relearning effective native tissue techniques for the transvaginal treatment of POP. While not perfect, they offer an effective nonmesh treatment option for many of our patients.

Sudhof LS, Shainker SA, Einerson BD. Tranexamic acid in the routine treatment of postpartum hemorrhage in the United States: a cost-effectiveness analysis. Am J Obstet Gynecol. Published online June 18, 2019. doi.org/10.1016/j.ajog.2019.06.030.

EXPERT COMMENTARY

Postpartum hemorrhage is a leading cause of morbidity and mortality in the United States. The World Maternal Antifibrinolytic (WOMAN) trial showed that the use of TXA, an antifibrinolytic agent, for PPH decreases hemorrhage-related mortality and laparotomy. Routine use of TXA for PPH has demonstrated cost-effectiveness in low-resource countries, where hemorrhage-related mortality rates are higher than in the United States. This study aimed to determine if routine use of TXA for PPH in the United States also is cost-effective.

Details of the study

Sudhof and colleagues conducted a decision-tree analysis to compare the cost-effectiveness of 3 strategies regarding routine use of TXA for PPH in the United States: no TXA, TXA given at any time, and TXA given within 3 hours of delivery.

Health care system perspective. In the primary analysis, the 3 strategies were evaluated from the perspective of the health care system. Outcomes included cost, number of laparotomies, and maternal deaths from delivery until 6 weeks postpartum. Rates of hemorrhage and related complications, as well as cost assumptions, were derived from multiple US-based studies. The relative risk reduction in death and laparotomy with TXA in the United States was assumed to be similar to that found in the WOMAN trial (19% and 36%, respectively).

Societal perspective. In the secondary analysis, the 3 TXA strategies were evaluated from the societal perspective, comparing quality-adjusted life-years (QALYs) and cost per QALY. For both the primary and secondary analyses, sensitivity analyses were performed across a range of values for each input.

Main findings. Tranexamic acid use would be cost saving if the relative risk reduction for maternal death with TXA was greater than approximately 5%, which is significantly lower than that seen in the WOMAN trial (19%). The primary analysis demonstrated that—assuming a 3% rate of PPH—giving TXA to women with PPH would save $11.3 million, prevent 334 laparotomies, and avert 9 maternal deaths annually in the United States. This cost saving nearly tripled if TXA was administered within 3 hours of delivery, with 5 additional maternal deaths prevented.

Secondary analysis incorporating QALYs also showed TXA use to be cost-effective. These findings held through various sensitivity analyses.

Continue to: Study strengths and limitations...

Study strengths and limitations

This study is novel in its critical objective to determine the cost-effectiveness of routine use of TXA for PPH in the United States. Robust modeling using Monte Carlo estimation and a variety of sensitivity analyses add reliability to the authors’ findings.

This work is limited, however, by the assumptions put into the authors’ models. For example, outcome data regarding effectiveness of TXA was taken from the WOMAN trial, which was not performed within the United States. In addition, it is difficult to quantify in dollars an event as profound as a maternal death. The authors recognize that they likely underestimate the “cost” of a maternal death, but that this underestimation would only increase the cost-effectiveness of TXA.

Finally, it is important to take into account that such economic analyses are helpful to inform institutional guidelines and hemorrhage protocols, but that patient-specific decision-making should be individualized based on the clinical scenario at hand.

Sudhof LS, Shainker SA, Einerson BD. Tranexamic acid in the routine treatment of postpartum hemorrhage in the United States: a cost-effectiveness analysis. Am J Obstet Gynecol. Published online June 18, 2019. doi.org/10.1016/j.ajog.2019.06.030.

EXPERT COMMENTARY

Postpartum hemorrhage is a leading cause of morbidity and mortality in the United States. The World Maternal Antifibrinolytic (WOMAN) trial showed that the use of TXA, an antifibrinolytic agent, for PPH decreases hemorrhage-related mortality and laparotomy. Routine use of TXA for PPH has demonstrated cost-effectiveness in low-resource countries, where hemorrhage-related mortality rates are higher than in the United States. This study aimed to determine if routine use of TXA for PPH in the United States also is cost-effective.

Details of the study

Sudhof and colleagues conducted a decision-tree analysis to compare the cost-effectiveness of 3 strategies regarding routine use of TXA for PPH in the United States: no TXA, TXA given at any time, and TXA given within 3 hours of delivery.

Health care system perspective. In the primary analysis, the 3 strategies were evaluated from the perspective of the health care system. Outcomes included cost, number of laparotomies, and maternal deaths from delivery until 6 weeks postpartum. Rates of hemorrhage and related complications, as well as cost assumptions, were derived from multiple US-based studies. The relative risk reduction in death and laparotomy with TXA in the United States was assumed to be similar to that found in the WOMAN trial (19% and 36%, respectively).

Societal perspective. In the secondary analysis, the 3 TXA strategies were evaluated from the societal perspective, comparing quality-adjusted life-years (QALYs) and cost per QALY. For both the primary and secondary analyses, sensitivity analyses were performed across a range of values for each input.

Main findings. Tranexamic acid use would be cost saving if the relative risk reduction for maternal death with TXA was greater than approximately 5%, which is significantly lower than that seen in the WOMAN trial (19%). The primary analysis demonstrated that—assuming a 3% rate of PPH—giving TXA to women with PPH would save $11.3 million, prevent 334 laparotomies, and avert 9 maternal deaths annually in the United States. This cost saving nearly tripled if TXA was administered within 3 hours of delivery, with 5 additional maternal deaths prevented.

Secondary analysis incorporating QALYs also showed TXA use to be cost-effective. These findings held through various sensitivity analyses.

Continue to: Study strengths and limitations...

Study strengths and limitations

This study is novel in its critical objective to determine the cost-effectiveness of routine use of TXA for PPH in the United States. Robust modeling using Monte Carlo estimation and a variety of sensitivity analyses add reliability to the authors’ findings.

This work is limited, however, by the assumptions put into the authors’ models. For example, outcome data regarding effectiveness of TXA was taken from the WOMAN trial, which was not performed within the United States. In addition, it is difficult to quantify in dollars an event as profound as a maternal death. The authors recognize that they likely underestimate the “cost” of a maternal death, but that this underestimation would only increase the cost-effectiveness of TXA.

Finally, it is important to take into account that such economic analyses are helpful to inform institutional guidelines and hemorrhage protocols, but that patient-specific decision-making should be individualized based on the clinical scenario at hand.

Sudhof LS, Shainker SA, Einerson BD. Tranexamic acid in the routine treatment of postpartum hemorrhage in the United States: a cost-effectiveness analysis. Am J Obstet Gynecol. Published online June 18, 2019. doi.org/10.1016/j.ajog.2019.06.030.

EXPERT COMMENTARY

Postpartum hemorrhage is a leading cause of morbidity and mortality in the United States. The World Maternal Antifibrinolytic (WOMAN) trial showed that the use of TXA, an antifibrinolytic agent, for PPH decreases hemorrhage-related mortality and laparotomy. Routine use of TXA for PPH has demonstrated cost-effectiveness in low-resource countries, where hemorrhage-related mortality rates are higher than in the United States. This study aimed to determine if routine use of TXA for PPH in the United States also is cost-effective.

Details of the study

Sudhof and colleagues conducted a decision-tree analysis to compare the cost-effectiveness of 3 strategies regarding routine use of TXA for PPH in the United States: no TXA, TXA given at any time, and TXA given within 3 hours of delivery.

Health care system perspective. In the primary analysis, the 3 strategies were evaluated from the perspective of the health care system. Outcomes included cost, number of laparotomies, and maternal deaths from delivery until 6 weeks postpartum. Rates of hemorrhage and related complications, as well as cost assumptions, were derived from multiple US-based studies. The relative risk reduction in death and laparotomy with TXA in the United States was assumed to be similar to that found in the WOMAN trial (19% and 36%, respectively).

Societal perspective. In the secondary analysis, the 3 TXA strategies were evaluated from the societal perspective, comparing quality-adjusted life-years (QALYs) and cost per QALY. For both the primary and secondary analyses, sensitivity analyses were performed across a range of values for each input.

Main findings. Tranexamic acid use would be cost saving if the relative risk reduction for maternal death with TXA was greater than approximately 5%, which is significantly lower than that seen in the WOMAN trial (19%). The primary analysis demonstrated that—assuming a 3% rate of PPH—giving TXA to women with PPH would save $11.3 million, prevent 334 laparotomies, and avert 9 maternal deaths annually in the United States. This cost saving nearly tripled if TXA was administered within 3 hours of delivery, with 5 additional maternal deaths prevented.

Secondary analysis incorporating QALYs also showed TXA use to be cost-effective. These findings held through various sensitivity analyses.

Continue to: Study strengths and limitations...

Study strengths and limitations

This study is novel in its critical objective to determine the cost-effectiveness of routine use of TXA for PPH in the United States. Robust modeling using Monte Carlo estimation and a variety of sensitivity analyses add reliability to the authors’ findings.

This work is limited, however, by the assumptions put into the authors’ models. For example, outcome data regarding effectiveness of TXA was taken from the WOMAN trial, which was not performed within the United States. In addition, it is difficult to quantify in dollars an event as profound as a maternal death. The authors recognize that they likely underestimate the “cost” of a maternal death, but that this underestimation would only increase the cost-effectiveness of TXA.

Finally, it is important to take into account that such economic analyses are helpful to inform institutional guidelines and hemorrhage protocols, but that patient-specific decision-making should be individualized based on the clinical scenario at hand.

Case 1 Induction at 39 weeks in a healthy nulliparous woman

A healthy 35-year-old woman (G1P0) at 39 weeks 0 days and with an uncomplicated pregnancy presents to your office for a routine prenatal visit. She inquires about scheduling an induction of labor, noting that she read a news story about induction at 39 weeks and that it might lower her chance of having a cesarean delivery (CD).

You perform a cervical exam—she is 1 cm dilated, 3 cm long, -2 station, posterior, and firm. You sweep her membranes after obtaining verbal consent. After describing the induction process, you explain that she might be hospitalized for several days before the birth given the need for cervical ripening. “You mean I need to stay in the hospital for the entire process?” she asks incredulously.
 

Over the past 20 years, the percentage of patients undergoing induction of labor (IOL) has increased from 10% to 25%.¹ This percentage likely will rise over time, particularly in the wake of a recent randomized controlled trial suggesting potential maternal benefits, such as reduced CD rate, for nulliparas induced at 39 weeks compared with expectant management.² Although there have not been any changes to guidelines for timing of IOL from such professional societies such as the American College of Obstetricians and Gynecologists (ACOG) or the Society for Maternal-Fetal Medicine, key considerations of rising IOL volume include patient experience, labor and delivery (L&D) units’ capacity and resources, and associated health care costs.

An essential part of successful induction involves patience. Induction can be a lengthy process, particularly for nulliparas with unripe cervices. Cervical ripening is a necessary component of successful labor induction, whether achieved mechanically or pharmacologically with synthetic prostaglandins, and it has been shown to lower the chance of CD.^3,4 However, achieving a ripe cervix is often the lengthiest part of an induction, and not uncommonly consumes 12 to 24 hours or more of inpatient time. Investigators have sought ways to make this process more expeditious. For example, the FOR-MOMI trial demonstrated that the induction-to-delivery time was several hours shorter when cervical ripening combined mechanical and pharmacologic approaches (Foley balloon plus misoprostol), compared with either method alone, without any increase in maternal or fetal complication rates.⁵

Better yet, what if admission to the L&D unit for IOL at term could be deferred until the cervix is ripe? A number of hospitals in the United States have successfully introduced outpatient cervical ripening, and several small observational and randomized controlled trials have reported good results in terms of safety, efficacy and time saved, and patient experience. Here, we will make the case that outpatient cervical ripening should be the standard of care for low-risk pregnancies.

Mechanical cervical ripening

Safety

Although data are limited on the safety, the authors of an ACOG Practice Bulletin suggest that, based on the available evidence of mechanical ripening in an inpatient setting, it is also appropriate in the outpatient setting.⁶ Unlike cervical ripening using prostaglandins, mechanical ripening is not associated with tachysystole, fetal intolerance of labor, or meconium staining.³ A cohort study of nearly 2,000 low-risk patients who underwent Foley catheter placement for cervical ripening using an outpatient protocol but monitored overnight as inpatients and evaluated for adverse outcomes found no CD for fetal distress, vaginal bleeding, placental abruption, or intrapartum stillbirth.⁷ The authors posited that, given this safety profile in the inpatient setting, that mechanical cervical ripening with a Foley catheter would be appropriate for outpatient use in low-risk populations. Other systematic reviews have been reassuring as well, with exceedingly low complication rates during inpatient mechanical cervical ripening.⁸ These data advocate for the evaluation of cervical ripening in the outpatient setting.

The evidence for outpatient mechanical ripening, although again limited, also has demonstrated safety. There does not appear to be an increased rate of maternal or neonatal complications, including infectious morbidity, postpartum hemorrhage, CD, operative vaginal delivery, or fetal distress.^9-12

Continue to: Efficacy and length-of-stay...

Efficacy and length-of-stay

Efficacy also generally has been shown to be similar when mechanical methods are used in the inpatient and outpatient settings. Small randomized trials of outpatient versus inpatient Foley catheter ripening have shown decreased length of stay (by 10 to 13 hours) and similar or less oxytocin use in the outpatient groups, as well as similar Bishop scores after cervical ripening and no difference in maternal or fetal outcomes.^9,11,13,14

One major concern with increasing IOL prevalence is the availability of hospital resources and the associated health care costs, given the known increased length of inpatient stay due to cervical ripening time. Admission to an L&D unit is resource intensive; the costs are similar to admission to an intensive care unit in many hospitals given its level of acuity and high nurse/patient ratio. However, given the safety of outpatient mechanical cervical ripening described above, we argue that routinely admitting low-risk patients for mechanical ripening constitutes a suboptimal use of costly resources.

Indeed, data suggest significant inpatient time savings if cervical ripening can be accomplished prior to admission. A cost-effectiveness analysis in the Netherlands demonstrated a nearly 1,000-euro decrease in cost per induction when Foley catheter induction was done on an outpatient basis.¹⁵ Interestingly, a recent trial confined to multiparas found no differences in hospital time when comparing outpatient ripening with Foley balloon alone with inpatient ripening with Foley balloon plus simultaneous oxytocin.¹⁰ This certainly merits further study, but it may be that the largest time- and cost-savings are among nulliparas.

Patient preferences

Relatively few studies specifically have addressed patient experiences with outpatient versus inpatient mechanical cervical ripening. Outpatient cervical ripening may provide patients with the benefits of being in the comfort of their own homes with their preferred support persons, increased mobility, more bodily autonomy, and satisfaction with their birthing process.

In a pilot trial involving 48 women, inpatient was compared with outpatient cervical ripening using a Foley balloon. Those in the outpatient group reported getting more rest, feeling less isolated, and having enough privacy. However, participants in both groups were equally satisfied and equally likely to recommend their method of induction to others.¹¹ Another study comparing outpatient versus inpatient Foley balloon cervical ripening found that 85% of patients who underwent outpatient ripening were satisfied with the induction method; however, no query or comparison was done with the inpatient group.¹² A trial comparing outpatient mechanical cervical ripening with inpatient misoprostol found that outpatient participants reported several hours more sleep and less pain.¹⁶ And in a discrete choice experiment of British gravidas, participants favored the option of outpatient cervical ripening, even if it meant an extra 1.4 trips to the hospital and over an hour of extra travel time.¹⁷

While these preliminary findings provide some insight that patients may prefer an outpatient approach to cervical ripening, more studies are needed to fully evaluate patient desires.

Continue to: Our approach to mechanical cervical ripening...

Our approach to mechanical cervical ripening

Most patients undergoing scheduled IOL are reasonable candidates for outpatient cervical ripening based on safety and efficacy. By definition, scheduling in advance implies that the provider has determined that outpatient management is reasonable until that date, and the plan for outpatient ripening need not prolong this period.

FIGURES 1 and 2 show protocols for our 2 hospital centers, which regularly allow for outpatient mechanical cervical ripening. In the process of protocol development, we identified absolute and relative contraindications to determine appropriate candidates. We exclude women who require inpatient management of medical or obstetric conditions (for example, women with severe preeclampsia or any condition requiring continuous fetal monitoring). We also do not routinely recommend outpatient cervical ripening to patients who do not have the necessary social conditions to make this process as safe as possible (including stable housing, reliable transportation, and a support person), although this occurs with some exceptions depending on individual patient situations.

Some examples of ideal candidates for outpatient mechanical cervical ripening include those undergoing elective or routine prolonged gestation inductions, or inductions for well-controlled, stable conditions (chronic hypertension and gestational diabetes). At one center, after thorough counseling and assessment, outpatient cervical ripening is also offered to patients with mild risk factors, including twins, prior low transverse CD, stable preeclampsia without severe features, isolated oligohydramnios with otherwise reassuring fetal status, and other similar conditions.

After mechanical cervical ripening placement (either Foley catheter or mechanical dilators), the clinician completes a postprocedure safety checklist and detailed procedure documentation, including number and type of foreign bodies placed. If there are any concerns regarding maternal or fetal well-being, the patient is sent to L&D for evaluation. If the procedure was tolerated well, the patient is discharged home, after a reactive postprocedure nonstress test is done, with detailed instructions for self-care, as well as with a list of symptoms that warrant prompt evaluation prior to scheduled induction time. In a large California hospital group following a similar protocol, only about 5% of women presented in labor before their scheduled induction.¹⁸

Case 2 Cervical ripening for labor preparation in low-risk pregnancy

A 32-year-old woman (G1P0) with an uncomplicated pregnancy at 40 weeks and 3 days presents to your office for a routine prenatal visit. Her vital signs are normal, and her fetus is vertex with an estimated fetal weight of 7.5 lb by Leopald’s maneuvers. You perform a cervical exam and find that her cervix is closed, long, and posterior.

You discuss with her your recommendation for induction of labor by 41 weeks, and she agrees. You also discuss the need for cervical ripening and recommend misoprostol given her closed cervix. You explain that several doses may be needed to get her cervix ready for labor, and she asks, “Do I have to stay in the hospital that whole time?”

Pharmacologic cervical ripening

Efficacy

There are multiple pharmacologic agents that can be used for ripening an unfavorable cervix. The main agents used in the United States are prostaglandins, either PGE1 (oral or vaginal misoprostol) or PGE2 in a gel or sustained-release vaginal insert (dinoprostone).

Outpatient misoprostol to avoid labor induction. Many studies have looked at outpatient misoprostol use as a “prophylactic measure” (to prevent the need for labor induction). For example, Gaffaney and colleagues showed that administering outpatient oral misoprostol (100 µg every 24 hours for up to 3 doses) after 40 weeks’ gestation to women with an unfavorable cervix significantly decreased the time to delivery by a day and a half.¹⁹ Similarly, PonMalar and colleagues demonstrated that administering 25 µg of vaginal misoprostol in a single dose as an outpatient after stripping the membranes significantly reduced time to delivery by 2 days.²⁰ And Stitely and colleagues found a significant reduction in the need for labor induction with the use of outpatient vaginal misoprostol. They administered up to 2 doses of misoprostol 25 µg vaginally every 24 hours for the 48 hours prior to a scheduled postdates induction and found a large reduction in the need for labor induction (11% vs 85%; P<.01).²¹

Continue to: Multiple protocols and regimens...

Multiple protocols and regimens have been studied but, overall, the findings suggest that administering outpatient misoprostol may shorten the time interval to spontaneous labor and decrease the need for a formal labor induction.^19-23

Inpatient compared with outpatient prostaglandin use. These trials of “prophylactic” misoprostol generally have compared outpatient administration of misoprostol with placebo. Prostaglandins are one of the most common methods of inpatient cervical ripening, so what about comparisons of inpatient cervical ripening with outpatient prostaglandin administration? There are a handful of studies that make this comparison.

Chang and colleagues looked retrospectively at inpatient and outpatient misoprostol and found that outpatient administration saved 3 to 5 hours on labor and delivery.²⁴ Biem and colleagues randomly assigned women to either inpatient cervical ripening with PGE2 intravaginal inserts or 1 hour of inpatient monitoring after PGE2 administration and then outpatient discharge until the onset of labor or for a nonstress test at 12 hours. They found that those who underwent outpatient ripening spent 8 hours less on labor and delivery and were more highly satisfied with the initial 12 hours of labor induction experience (56% vs 39%; P<.01).²⁵

The largest randomized controlled trial conducted to study outpatient prostaglandin use was the OPRA study (involving 827 women). Investigators compared inpatient to outpatient PGE2 intravaginal gel.²⁶ The primary outcome was total oxytocin administration, which was not different between groups. The study was underpowered, however, as 50% of women labored spontaneously postrandomization. But in the outpatient arm, less than half of the women required additional inpatient ripening, and nearly 40% returned in spontaneous labor, suggesting that outpatient prostaglandin administration may indeed save women a significant amount of time on labor and delivery.

Safety

The safety of outpatient administration of prostaglandins is the biggest concern, especially since, when prostaglandins are compared to outpatient Foley catheter use, Foleys are overall associated with less tachysystole, fetal intolerance, and meconium-stained fluid.³ Foley catheter use for cervical ripening may not be an appropriate choice for all patients, however. For instance, our case patient has a closed cervix, which could make Foley insertion uncomfortable or even impossible. Misoprostol use also offers the potential for flexibility in cervical ripening protocols as patients need not return for Foley balloon removal and indeed labor induction need not take place immediately after administration of misoprostol.

Patients also may prefer outpatient cervical ripening with misoprostol over a Foley. There are some data to suggest that women, overall, have a preference toward prostaglandins; in the PROBAAT-II trial, which compared inpatient oral misoprostol to Foley catheter for cervical ripening, 12% of women in the Foley arm would have preferred another method of induction (vs 6% in the misoprostol arm; P = .02).²⁷ This preference may be magnified in an outpatient setting.

But, again, is outpatient administration of prostaglandins safe? The published trials thus far have not reported an increase in out-of-hospital deliveries or adverse fetal outcomes. However, studies have been of limited size to see more rare outcomes. Unfortunately, an adequately powered study to demonstrate safety is likely never to be accomplished, given that if used responsibly (in low-risk patients with adequate monitoring after administration) the incidence of adverse fetal outcomes during the at-home portion of cervical ripening is likely to be very low. With responsible use, outpatient administration of prostaglandins should be safe. Women are monitored after misoprostol administration and are not sent home if there are any concerns for fetal distress or if frequent contractions continue. Misoprostol reaches maximum blood concentration 30 minutes after oral administration and 70 to 80 minutes after vaginal administration.²⁸ After this time, if contractions start to intensify it is likely that misoprostol has triggered spontaneous labor. In this setting, women are routinely allowed to spontaneously labor at home. One may even argue that outpatient misoprostol could lead to improved safety, as women essentially have a contraction stress test prior to spontaneous labor, and misoprostol administration as an outpatient, as opposed to as an inpatient, may allow for longer time intervals between doses, which could prevent dose stacking.

Continue to: Our approach to pharmacologic cervical ripening...

Our approach to pharmacologic cervical ripening

Our hospital has been conducting outpatient cervical ripening using vaginal misoprostol for more than 15 years without any known adverse safety concerns (FIGURE 3). Women with a low-risk, singleton pregnancy between 39+0 and 40+6 weeks are potential candidates for outpatient ripening. The majority of outpatient inductions are done electively without any medical indication. Women with stable, minor risk factors (such as diet-controlled gestational diabetes) also may be candidates at their clinician’s discretion. Patients are monitored either in our L&D triage area or in our outpatient antenatal unit; both units are in the same building. One clinician offers outpatient misoprostol in the office, across the street from L&D. We allow for clinician flexibility after administration. Some clinicians do 1 or 2 doses of outpatient cervical ripening in a day prior to a scheduled inpatient induction the next day. Some do multiple daily doses over the course of a week.

Conclusion

While the data continue to be limited, we strongly believe there is sufficient quality evidence from a safety and efficacy perspective to support implementation and evaluation of outpatient cervical ripening protocols for low-risk pregnancies. In the setting of renewed commitments to reducing suboptimal health care costs and utilization as well as increasing patient satisfaction and control in their birthing experiences, we posit it is the responsibility of obstetricians, L&D leadership, and health care institutions to explore the implementation of outpatient cervical ripening for appropriate candidates in their settings.

Case 1 Induction at 39 weeks in a healthy nulliparous woman

A healthy 35-year-old woman (G1P0) at 39 weeks 0 days and with an uncomplicated pregnancy presents to your office for a routine prenatal visit. She inquires about scheduling an induction of labor, noting that she read a news story about induction at 39 weeks and that it might lower her chance of having a cesarean delivery (CD).

You perform a cervical exam—she is 1 cm dilated, 3 cm long, -2 station, posterior, and firm. You sweep her membranes after obtaining verbal consent. After describing the induction process, you explain that she might be hospitalized for several days before the birth given the need for cervical ripening. “You mean I need to stay in the hospital for the entire process?” she asks incredulously.
 

Over the past 20 years, the percentage of patients undergoing induction of labor (IOL) has increased from 10% to 25%.¹ This percentage likely will rise over time, particularly in the wake of a recent randomized controlled trial suggesting potential maternal benefits, such as reduced CD rate, for nulliparas induced at 39 weeks compared with expectant management.² Although there have not been any changes to guidelines for timing of IOL from such professional societies such as the American College of Obstetricians and Gynecologists (ACOG) or the Society for Maternal-Fetal Medicine, key considerations of rising IOL volume include patient experience, labor and delivery (L&D) units’ capacity and resources, and associated health care costs.

An essential part of successful induction involves patience. Induction can be a lengthy process, particularly for nulliparas with unripe cervices. Cervical ripening is a necessary component of successful labor induction, whether achieved mechanically or pharmacologically with synthetic prostaglandins, and it has been shown to lower the chance of CD.^3,4 However, achieving a ripe cervix is often the lengthiest part of an induction, and not uncommonly consumes 12 to 24 hours or more of inpatient time. Investigators have sought ways to make this process more expeditious. For example, the FOR-MOMI trial demonstrated that the induction-to-delivery time was several hours shorter when cervical ripening combined mechanical and pharmacologic approaches (Foley balloon plus misoprostol), compared with either method alone, without any increase in maternal or fetal complication rates.⁵

Better yet, what if admission to the L&D unit for IOL at term could be deferred until the cervix is ripe? A number of hospitals in the United States have successfully introduced outpatient cervical ripening, and several small observational and randomized controlled trials have reported good results in terms of safety, efficacy and time saved, and patient experience. Here, we will make the case that outpatient cervical ripening should be the standard of care for low-risk pregnancies.

Mechanical cervical ripening

Safety

Although data are limited on the safety, the authors of an ACOG Practice Bulletin suggest that, based on the available evidence of mechanical ripening in an inpatient setting, it is also appropriate in the outpatient setting.⁶ Unlike cervical ripening using prostaglandins, mechanical ripening is not associated with tachysystole, fetal intolerance of labor, or meconium staining.³ A cohort study of nearly 2,000 low-risk patients who underwent Foley catheter placement for cervical ripening using an outpatient protocol but monitored overnight as inpatients and evaluated for adverse outcomes found no CD for fetal distress, vaginal bleeding, placental abruption, or intrapartum stillbirth.⁷ The authors posited that, given this safety profile in the inpatient setting, that mechanical cervical ripening with a Foley catheter would be appropriate for outpatient use in low-risk populations. Other systematic reviews have been reassuring as well, with exceedingly low complication rates during inpatient mechanical cervical ripening.⁸ These data advocate for the evaluation of cervical ripening in the outpatient setting.

The evidence for outpatient mechanical ripening, although again limited, also has demonstrated safety. There does not appear to be an increased rate of maternal or neonatal complications, including infectious morbidity, postpartum hemorrhage, CD, operative vaginal delivery, or fetal distress.^9-12

Continue to: Efficacy and length-of-stay...

Efficacy and length-of-stay

Efficacy also generally has been shown to be similar when mechanical methods are used in the inpatient and outpatient settings. Small randomized trials of outpatient versus inpatient Foley catheter ripening have shown decreased length of stay (by 10 to 13 hours) and similar or less oxytocin use in the outpatient groups, as well as similar Bishop scores after cervical ripening and no difference in maternal or fetal outcomes.^9,11,13,14

One major concern with increasing IOL prevalence is the availability of hospital resources and the associated health care costs, given the known increased length of inpatient stay due to cervical ripening time. Admission to an L&D unit is resource intensive; the costs are similar to admission to an intensive care unit in many hospitals given its level of acuity and high nurse/patient ratio. However, given the safety of outpatient mechanical cervical ripening described above, we argue that routinely admitting low-risk patients for mechanical ripening constitutes a suboptimal use of costly resources.

Indeed, data suggest significant inpatient time savings if cervical ripening can be accomplished prior to admission. A cost-effectiveness analysis in the Netherlands demonstrated a nearly 1,000-euro decrease in cost per induction when Foley catheter induction was done on an outpatient basis.¹⁵ Interestingly, a recent trial confined to multiparas found no differences in hospital time when comparing outpatient ripening with Foley balloon alone with inpatient ripening with Foley balloon plus simultaneous oxytocin.¹⁰ This certainly merits further study, but it may be that the largest time- and cost-savings are among nulliparas.

Patient preferences

Relatively few studies specifically have addressed patient experiences with outpatient versus inpatient mechanical cervical ripening. Outpatient cervical ripening may provide patients with the benefits of being in the comfort of their own homes with their preferred support persons, increased mobility, more bodily autonomy, and satisfaction with their birthing process.

In a pilot trial involving 48 women, inpatient was compared with outpatient cervical ripening using a Foley balloon. Those in the outpatient group reported getting more rest, feeling less isolated, and having enough privacy. However, participants in both groups were equally satisfied and equally likely to recommend their method of induction to others.¹¹ Another study comparing outpatient versus inpatient Foley balloon cervical ripening found that 85% of patients who underwent outpatient ripening were satisfied with the induction method; however, no query or comparison was done with the inpatient group.¹² A trial comparing outpatient mechanical cervical ripening with inpatient misoprostol found that outpatient participants reported several hours more sleep and less pain.¹⁶ And in a discrete choice experiment of British gravidas, participants favored the option of outpatient cervical ripening, even if it meant an extra 1.4 trips to the hospital and over an hour of extra travel time.¹⁷

While these preliminary findings provide some insight that patients may prefer an outpatient approach to cervical ripening, more studies are needed to fully evaluate patient desires.

Continue to: Our approach to mechanical cervical ripening...

Our approach to mechanical cervical ripening

Most patients undergoing scheduled IOL are reasonable candidates for outpatient cervical ripening based on safety and efficacy. By definition, scheduling in advance implies that the provider has determined that outpatient management is reasonable until that date, and the plan for outpatient ripening need not prolong this period.

FIGURES 1 and 2 show protocols for our 2 hospital centers, which regularly allow for outpatient mechanical cervical ripening. In the process of protocol development, we identified absolute and relative contraindications to determine appropriate candidates. We exclude women who require inpatient management of medical or obstetric conditions (for example, women with severe preeclampsia or any condition requiring continuous fetal monitoring). We also do not routinely recommend outpatient cervical ripening to patients who do not have the necessary social conditions to make this process as safe as possible (including stable housing, reliable transportation, and a support person), although this occurs with some exceptions depending on individual patient situations.

Some examples of ideal candidates for outpatient mechanical cervical ripening include those undergoing elective or routine prolonged gestation inductions, or inductions for well-controlled, stable conditions (chronic hypertension and gestational diabetes). At one center, after thorough counseling and assessment, outpatient cervical ripening is also offered to patients with mild risk factors, including twins, prior low transverse CD, stable preeclampsia without severe features, isolated oligohydramnios with otherwise reassuring fetal status, and other similar conditions.

After mechanical cervical ripening placement (either Foley catheter or mechanical dilators), the clinician completes a postprocedure safety checklist and detailed procedure documentation, including number and type of foreign bodies placed. If there are any concerns regarding maternal or fetal well-being, the patient is sent to L&D for evaluation. If the procedure was tolerated well, the patient is discharged home, after a reactive postprocedure nonstress test is done, with detailed instructions for self-care, as well as with a list of symptoms that warrant prompt evaluation prior to scheduled induction time. In a large California hospital group following a similar protocol, only about 5% of women presented in labor before their scheduled induction.¹⁸

Case 2 Cervical ripening for labor preparation in low-risk pregnancy

A 32-year-old woman (G1P0) with an uncomplicated pregnancy at 40 weeks and 3 days presents to your office for a routine prenatal visit. Her vital signs are normal, and her fetus is vertex with an estimated fetal weight of 7.5 lb by Leopald’s maneuvers. You perform a cervical exam and find that her cervix is closed, long, and posterior.

You discuss with her your recommendation for induction of labor by 41 weeks, and she agrees. You also discuss the need for cervical ripening and recommend misoprostol given her closed cervix. You explain that several doses may be needed to get her cervix ready for labor, and she asks, “Do I have to stay in the hospital that whole time?”

Pharmacologic cervical ripening

Efficacy

There are multiple pharmacologic agents that can be used for ripening an unfavorable cervix. The main agents used in the United States are prostaglandins, either PGE1 (oral or vaginal misoprostol) or PGE2 in a gel or sustained-release vaginal insert (dinoprostone).

Outpatient misoprostol to avoid labor induction. Many studies have looked at outpatient misoprostol use as a “prophylactic measure” (to prevent the need for labor induction). For example, Gaffaney and colleagues showed that administering outpatient oral misoprostol (100 µg every 24 hours for up to 3 doses) after 40 weeks’ gestation to women with an unfavorable cervix significantly decreased the time to delivery by a day and a half.¹⁹ Similarly, PonMalar and colleagues demonstrated that administering 25 µg of vaginal misoprostol in a single dose as an outpatient after stripping the membranes significantly reduced time to delivery by 2 days.²⁰ And Stitely and colleagues found a significant reduction in the need for labor induction with the use of outpatient vaginal misoprostol. They administered up to 2 doses of misoprostol 25 µg vaginally every 24 hours for the 48 hours prior to a scheduled postdates induction and found a large reduction in the need for labor induction (11% vs 85%; P<.01).²¹

Continue to: Multiple protocols and regimens...

Multiple protocols and regimens have been studied but, overall, the findings suggest that administering outpatient misoprostol may shorten the time interval to spontaneous labor and decrease the need for a formal labor induction.^19-23

Inpatient compared with outpatient prostaglandin use. These trials of “prophylactic” misoprostol generally have compared outpatient administration of misoprostol with placebo. Prostaglandins are one of the most common methods of inpatient cervical ripening, so what about comparisons of inpatient cervical ripening with outpatient prostaglandin administration? There are a handful of studies that make this comparison.

Chang and colleagues looked retrospectively at inpatient and outpatient misoprostol and found that outpatient administration saved 3 to 5 hours on labor and delivery.²⁴ Biem and colleagues randomly assigned women to either inpatient cervical ripening with PGE2 intravaginal inserts or 1 hour of inpatient monitoring after PGE2 administration and then outpatient discharge until the onset of labor or for a nonstress test at 12 hours. They found that those who underwent outpatient ripening spent 8 hours less on labor and delivery and were more highly satisfied with the initial 12 hours of labor induction experience (56% vs 39%; P<.01).²⁵

The largest randomized controlled trial conducted to study outpatient prostaglandin use was the OPRA study (involving 827 women). Investigators compared inpatient to outpatient PGE2 intravaginal gel.²⁶ The primary outcome was total oxytocin administration, which was not different between groups. The study was underpowered, however, as 50% of women labored spontaneously postrandomization. But in the outpatient arm, less than half of the women required additional inpatient ripening, and nearly 40% returned in spontaneous labor, suggesting that outpatient prostaglandin administration may indeed save women a significant amount of time on labor and delivery.

Safety

The safety of outpatient administration of prostaglandins is the biggest concern, especially since, when prostaglandins are compared to outpatient Foley catheter use, Foleys are overall associated with less tachysystole, fetal intolerance, and meconium-stained fluid.³ Foley catheter use for cervical ripening may not be an appropriate choice for all patients, however. For instance, our case patient has a closed cervix, which could make Foley insertion uncomfortable or even impossible. Misoprostol use also offers the potential for flexibility in cervical ripening protocols as patients need not return for Foley balloon removal and indeed labor induction need not take place immediately after administration of misoprostol.

Patients also may prefer outpatient cervical ripening with misoprostol over a Foley. There are some data to suggest that women, overall, have a preference toward prostaglandins; in the PROBAAT-II trial, which compared inpatient oral misoprostol to Foley catheter for cervical ripening, 12% of women in the Foley arm would have preferred another method of induction (vs 6% in the misoprostol arm; P = .02).²⁷ This preference may be magnified in an outpatient setting.

But, again, is outpatient administration of prostaglandins safe? The published trials thus far have not reported an increase in out-of-hospital deliveries or adverse fetal outcomes. However, studies have been of limited size to see more rare outcomes. Unfortunately, an adequately powered study to demonstrate safety is likely never to be accomplished, given that if used responsibly (in low-risk patients with adequate monitoring after administration) the incidence of adverse fetal outcomes during the at-home portion of cervical ripening is likely to be very low. With responsible use, outpatient administration of prostaglandins should be safe. Women are monitored after misoprostol administration and are not sent home if there are any concerns for fetal distress or if frequent contractions continue. Misoprostol reaches maximum blood concentration 30 minutes after oral administration and 70 to 80 minutes after vaginal administration.²⁸ After this time, if contractions start to intensify it is likely that misoprostol has triggered spontaneous labor. In this setting, women are routinely allowed to spontaneously labor at home. One may even argue that outpatient misoprostol could lead to improved safety, as women essentially have a contraction stress test prior to spontaneous labor, and misoprostol administration as an outpatient, as opposed to as an inpatient, may allow for longer time intervals between doses, which could prevent dose stacking.

Continue to: Our approach to pharmacologic cervical ripening...

Our approach to pharmacologic cervical ripening

Our hospital has been conducting outpatient cervical ripening using vaginal misoprostol for more than 15 years without any known adverse safety concerns (FIGURE 3). Women with a low-risk, singleton pregnancy between 39+0 and 40+6 weeks are potential candidates for outpatient ripening. The majority of outpatient inductions are done electively without any medical indication. Women with stable, minor risk factors (such as diet-controlled gestational diabetes) also may be candidates at their clinician’s discretion. Patients are monitored either in our L&D triage area or in our outpatient antenatal unit; both units are in the same building. One clinician offers outpatient misoprostol in the office, across the street from L&D. We allow for clinician flexibility after administration. Some clinicians do 1 or 2 doses of outpatient cervical ripening in a day prior to a scheduled inpatient induction the next day. Some do multiple daily doses over the course of a week.

Conclusion

While the data continue to be limited, we strongly believe there is sufficient quality evidence from a safety and efficacy perspective to support implementation and evaluation of outpatient cervical ripening protocols for low-risk pregnancies. In the setting of renewed commitments to reducing suboptimal health care costs and utilization as well as increasing patient satisfaction and control in their birthing experiences, we posit it is the responsibility of obstetricians, L&D leadership, and health care institutions to explore the implementation of outpatient cervical ripening for appropriate candidates in their settings.

Case 1 Induction at 39 weeks in a healthy nulliparous woman

A healthy 35-year-old woman (G1P0) at 39 weeks 0 days and with an uncomplicated pregnancy presents to your office for a routine prenatal visit. She inquires about scheduling an induction of labor, noting that she read a news story about induction at 39 weeks and that it might lower her chance of having a cesarean delivery (CD).

You perform a cervical exam—she is 1 cm dilated, 3 cm long, -2 station, posterior, and firm. You sweep her membranes after obtaining verbal consent. After describing the induction process, you explain that she might be hospitalized for several days before the birth given the need for cervical ripening. “You mean I need to stay in the hospital for the entire process?” she asks incredulously.
 

Over the past 20 years, the percentage of patients undergoing induction of labor (IOL) has increased from 10% to 25%.¹ This percentage likely will rise over time, particularly in the wake of a recent randomized controlled trial suggesting potential maternal benefits, such as reduced CD rate, for nulliparas induced at 39 weeks compared with expectant management.² Although there have not been any changes to guidelines for timing of IOL from such professional societies such as the American College of Obstetricians and Gynecologists (ACOG) or the Society for Maternal-Fetal Medicine, key considerations of rising IOL volume include patient experience, labor and delivery (L&D) units’ capacity and resources, and associated health care costs.

An essential part of successful induction involves patience. Induction can be a lengthy process, particularly for nulliparas with unripe cervices. Cervical ripening is a necessary component of successful labor induction, whether achieved mechanically or pharmacologically with synthetic prostaglandins, and it has been shown to lower the chance of CD.^3,4 However, achieving a ripe cervix is often the lengthiest part of an induction, and not uncommonly consumes 12 to 24 hours or more of inpatient time. Investigators have sought ways to make this process more expeditious. For example, the FOR-MOMI trial demonstrated that the induction-to-delivery time was several hours shorter when cervical ripening combined mechanical and pharmacologic approaches (Foley balloon plus misoprostol), compared with either method alone, without any increase in maternal or fetal complication rates.⁵

Better yet, what if admission to the L&D unit for IOL at term could be deferred until the cervix is ripe? A number of hospitals in the United States have successfully introduced outpatient cervical ripening, and several small observational and randomized controlled trials have reported good results in terms of safety, efficacy and time saved, and patient experience. Here, we will make the case that outpatient cervical ripening should be the standard of care for low-risk pregnancies.

Mechanical cervical ripening

Safety

Although data are limited on the safety, the authors of an ACOG Practice Bulletin suggest that, based on the available evidence of mechanical ripening in an inpatient setting, it is also appropriate in the outpatient setting.⁶ Unlike cervical ripening using prostaglandins, mechanical ripening is not associated with tachysystole, fetal intolerance of labor, or meconium staining.³ A cohort study of nearly 2,000 low-risk patients who underwent Foley catheter placement for cervical ripening using an outpatient protocol but monitored overnight as inpatients and evaluated for adverse outcomes found no CD for fetal distress, vaginal bleeding, placental abruption, or intrapartum stillbirth.⁷ The authors posited that, given this safety profile in the inpatient setting, that mechanical cervical ripening with a Foley catheter would be appropriate for outpatient use in low-risk populations. Other systematic reviews have been reassuring as well, with exceedingly low complication rates during inpatient mechanical cervical ripening.⁸ These data advocate for the evaluation of cervical ripening in the outpatient setting.

The evidence for outpatient mechanical ripening, although again limited, also has demonstrated safety. There does not appear to be an increased rate of maternal or neonatal complications, including infectious morbidity, postpartum hemorrhage, CD, operative vaginal delivery, or fetal distress.^9-12

Continue to: Efficacy and length-of-stay...

Efficacy and length-of-stay

Efficacy also generally has been shown to be similar when mechanical methods are used in the inpatient and outpatient settings. Small randomized trials of outpatient versus inpatient Foley catheter ripening have shown decreased length of stay (by 10 to 13 hours) and similar or less oxytocin use in the outpatient groups, as well as similar Bishop scores after cervical ripening and no difference in maternal or fetal outcomes.^9,11,13,14

One major concern with increasing IOL prevalence is the availability of hospital resources and the associated health care costs, given the known increased length of inpatient stay due to cervical ripening time. Admission to an L&D unit is resource intensive; the costs are similar to admission to an intensive care unit in many hospitals given its level of acuity and high nurse/patient ratio. However, given the safety of outpatient mechanical cervical ripening described above, we argue that routinely admitting low-risk patients for mechanical ripening constitutes a suboptimal use of costly resources.

Indeed, data suggest significant inpatient time savings if cervical ripening can be accomplished prior to admission. A cost-effectiveness analysis in the Netherlands demonstrated a nearly 1,000-euro decrease in cost per induction when Foley catheter induction was done on an outpatient basis.¹⁵ Interestingly, a recent trial confined to multiparas found no differences in hospital time when comparing outpatient ripening with Foley balloon alone with inpatient ripening with Foley balloon plus simultaneous oxytocin.¹⁰ This certainly merits further study, but it may be that the largest time- and cost-savings are among nulliparas.

Patient preferences

Relatively few studies specifically have addressed patient experiences with outpatient versus inpatient mechanical cervical ripening. Outpatient cervical ripening may provide patients with the benefits of being in the comfort of their own homes with their preferred support persons, increased mobility, more bodily autonomy, and satisfaction with their birthing process.

In a pilot trial involving 48 women, inpatient was compared with outpatient cervical ripening using a Foley balloon. Those in the outpatient group reported getting more rest, feeling less isolated, and having enough privacy. However, participants in both groups were equally satisfied and equally likely to recommend their method of induction to others.¹¹ Another study comparing outpatient versus inpatient Foley balloon cervical ripening found that 85% of patients who underwent outpatient ripening were satisfied with the induction method; however, no query or comparison was done with the inpatient group.¹² A trial comparing outpatient mechanical cervical ripening with inpatient misoprostol found that outpatient participants reported several hours more sleep and less pain.¹⁶ And in a discrete choice experiment of British gravidas, participants favored the option of outpatient cervical ripening, even if it meant an extra 1.4 trips to the hospital and over an hour of extra travel time.¹⁷

While these preliminary findings provide some insight that patients may prefer an outpatient approach to cervical ripening, more studies are needed to fully evaluate patient desires.

Continue to: Our approach to mechanical cervical ripening...

Our approach to mechanical cervical ripening

Most patients undergoing scheduled IOL are reasonable candidates for outpatient cervical ripening based on safety and efficacy. By definition, scheduling in advance implies that the provider has determined that outpatient management is reasonable until that date, and the plan for outpatient ripening need not prolong this period.

FIGURES 1 and 2 show protocols for our 2 hospital centers, which regularly allow for outpatient mechanical cervical ripening. In the process of protocol development, we identified absolute and relative contraindications to determine appropriate candidates. We exclude women who require inpatient management of medical or obstetric conditions (for example, women with severe preeclampsia or any condition requiring continuous fetal monitoring). We also do not routinely recommend outpatient cervical ripening to patients who do not have the necessary social conditions to make this process as safe as possible (including stable housing, reliable transportation, and a support person), although this occurs with some exceptions depending on individual patient situations.

Some examples of ideal candidates for outpatient mechanical cervical ripening include those undergoing elective or routine prolonged gestation inductions, or inductions for well-controlled, stable conditions (chronic hypertension and gestational diabetes). At one center, after thorough counseling and assessment, outpatient cervical ripening is also offered to patients with mild risk factors, including twins, prior low transverse CD, stable preeclampsia without severe features, isolated oligohydramnios with otherwise reassuring fetal status, and other similar conditions.

After mechanical cervical ripening placement (either Foley catheter or mechanical dilators), the clinician completes a postprocedure safety checklist and detailed procedure documentation, including number and type of foreign bodies placed. If there are any concerns regarding maternal or fetal well-being, the patient is sent to L&D for evaluation. If the procedure was tolerated well, the patient is discharged home, after a reactive postprocedure nonstress test is done, with detailed instructions for self-care, as well as with a list of symptoms that warrant prompt evaluation prior to scheduled induction time. In a large California hospital group following a similar protocol, only about 5% of women presented in labor before their scheduled induction.¹⁸

Case 2 Cervical ripening for labor preparation in low-risk pregnancy

A 32-year-old woman (G1P0) with an uncomplicated pregnancy at 40 weeks and 3 days presents to your office for a routine prenatal visit. Her vital signs are normal, and her fetus is vertex with an estimated fetal weight of 7.5 lb by Leopald’s maneuvers. You perform a cervical exam and find that her cervix is closed, long, and posterior.

You discuss with her your recommendation for induction of labor by 41 weeks, and she agrees. You also discuss the need for cervical ripening and recommend misoprostol given her closed cervix. You explain that several doses may be needed to get her cervix ready for labor, and she asks, “Do I have to stay in the hospital that whole time?”

Pharmacologic cervical ripening

Efficacy

There are multiple pharmacologic agents that can be used for ripening an unfavorable cervix. The main agents used in the United States are prostaglandins, either PGE1 (oral or vaginal misoprostol) or PGE2 in a gel or sustained-release vaginal insert (dinoprostone).

Outpatient misoprostol to avoid labor induction. Many studies have looked at outpatient misoprostol use as a “prophylactic measure” (to prevent the need for labor induction). For example, Gaffaney and colleagues showed that administering outpatient oral misoprostol (100 µg every 24 hours for up to 3 doses) after 40 weeks’ gestation to women with an unfavorable cervix significantly decreased the time to delivery by a day and a half.¹⁹ Similarly, PonMalar and colleagues demonstrated that administering 25 µg of vaginal misoprostol in a single dose as an outpatient after stripping the membranes significantly reduced time to delivery by 2 days.²⁰ And Stitely and colleagues found a significant reduction in the need for labor induction with the use of outpatient vaginal misoprostol. They administered up to 2 doses of misoprostol 25 µg vaginally every 24 hours for the 48 hours prior to a scheduled postdates induction and found a large reduction in the need for labor induction (11% vs 85%; P<.01).²¹

Continue to: Multiple protocols and regimens...

Multiple protocols and regimens have been studied but, overall, the findings suggest that administering outpatient misoprostol may shorten the time interval to spontaneous labor and decrease the need for a formal labor induction.^19-23

Inpatient compared with outpatient prostaglandin use. These trials of “prophylactic” misoprostol generally have compared outpatient administration of misoprostol with placebo. Prostaglandins are one of the most common methods of inpatient cervical ripening, so what about comparisons of inpatient cervical ripening with outpatient prostaglandin administration? There are a handful of studies that make this comparison.

Chang and colleagues looked retrospectively at inpatient and outpatient misoprostol and found that outpatient administration saved 3 to 5 hours on labor and delivery.²⁴ Biem and colleagues randomly assigned women to either inpatient cervical ripening with PGE2 intravaginal inserts or 1 hour of inpatient monitoring after PGE2 administration and then outpatient discharge until the onset of labor or for a nonstress test at 12 hours. They found that those who underwent outpatient ripening spent 8 hours less on labor and delivery and were more highly satisfied with the initial 12 hours of labor induction experience (56% vs 39%; P<.01).²⁵

The largest randomized controlled trial conducted to study outpatient prostaglandin use was the OPRA study (involving 827 women). Investigators compared inpatient to outpatient PGE2 intravaginal gel.²⁶ The primary outcome was total oxytocin administration, which was not different between groups. The study was underpowered, however, as 50% of women labored spontaneously postrandomization. But in the outpatient arm, less than half of the women required additional inpatient ripening, and nearly 40% returned in spontaneous labor, suggesting that outpatient prostaglandin administration may indeed save women a significant amount of time on labor and delivery.

Safety

The safety of outpatient administration of prostaglandins is the biggest concern, especially since, when prostaglandins are compared to outpatient Foley catheter use, Foleys are overall associated with less tachysystole, fetal intolerance, and meconium-stained fluid.³ Foley catheter use for cervical ripening may not be an appropriate choice for all patients, however. For instance, our case patient has a closed cervix, which could make Foley insertion uncomfortable or even impossible. Misoprostol use also offers the potential for flexibility in cervical ripening protocols as patients need not return for Foley balloon removal and indeed labor induction need not take place immediately after administration of misoprostol.

Patients also may prefer outpatient cervical ripening with misoprostol over a Foley. There are some data to suggest that women, overall, have a preference toward prostaglandins; in the PROBAAT-II trial, which compared inpatient oral misoprostol to Foley catheter for cervical ripening, 12% of women in the Foley arm would have preferred another method of induction (vs 6% in the misoprostol arm; P = .02).²⁷ This preference may be magnified in an outpatient setting.

But, again, is outpatient administration of prostaglandins safe? The published trials thus far have not reported an increase in out-of-hospital deliveries or adverse fetal outcomes. However, studies have been of limited size to see more rare outcomes. Unfortunately, an adequately powered study to demonstrate safety is likely never to be accomplished, given that if used responsibly (in low-risk patients with adequate monitoring after administration) the incidence of adverse fetal outcomes during the at-home portion of cervical ripening is likely to be very low. With responsible use, outpatient administration of prostaglandins should be safe. Women are monitored after misoprostol administration and are not sent home if there are any concerns for fetal distress or if frequent contractions continue. Misoprostol reaches maximum blood concentration 30 minutes after oral administration and 70 to 80 minutes after vaginal administration.²⁸ After this time, if contractions start to intensify it is likely that misoprostol has triggered spontaneous labor. In this setting, women are routinely allowed to spontaneously labor at home. One may even argue that outpatient misoprostol could lead to improved safety, as women essentially have a contraction stress test prior to spontaneous labor, and misoprostol administration as an outpatient, as opposed to as an inpatient, may allow for longer time intervals between doses, which could prevent dose stacking.

Continue to: Our approach to pharmacologic cervical ripening...

Our approach to pharmacologic cervical ripening

Our hospital has been conducting outpatient cervical ripening using vaginal misoprostol for more than 15 years without any known adverse safety concerns (FIGURE 3). Women with a low-risk, singleton pregnancy between 39+0 and 40+6 weeks are potential candidates for outpatient ripening. The majority of outpatient inductions are done electively without any medical indication. Women with stable, minor risk factors (such as diet-controlled gestational diabetes) also may be candidates at their clinician’s discretion. Patients are monitored either in our L&D triage area or in our outpatient antenatal unit; both units are in the same building. One clinician offers outpatient misoprostol in the office, across the street from L&D. We allow for clinician flexibility after administration. Some clinicians do 1 or 2 doses of outpatient cervical ripening in a day prior to a scheduled inpatient induction the next day. Some do multiple daily doses over the course of a week.

Conclusion

While the data continue to be limited, we strongly believe there is sufficient quality evidence from a safety and efficacy perspective to support implementation and evaluation of outpatient cervical ripening protocols for low-risk pregnancies. In the setting of renewed commitments to reducing suboptimal health care costs and utilization as well as increasing patient satisfaction and control in their birthing experiences, we posit it is the responsibility of obstetricians, L&D leadership, and health care institutions to explore the implementation of outpatient cervical ripening for appropriate candidates in their settings.

Major depressive disorder (MDD) is a significant pediatric health problem, with a lifetime prevalence as high as 20% by the end of adolescence.^1-3 Major depressive disorder in adolescence is associated with significant morbidity, including poor social functioning, school difficulties, early pregnancy, and increased risk of physical illness and substance abuse.^4-6 It is also linked with significant mortality, with increased risk for suicide, which is now the second leading cause of death in individuals age 10 to 24 years.^1,7,8

As their name suggests, antidepressants comprise a group of medications that are used to treat MDD; they are also, however, first-line agents for generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD) in adults. Anxiety disorders (including GAD and other anxiety diagnoses) and PTSD are also common in childhood and adolescence with a combined lifetime prevalence ranging from 15% to 30%.^9,10 These disorders are also associated with increased risk of suicide.¹¹ For all of these disorders, depending on the severity of presentation and the preference of the patient, treatments are often a combination of psychotherapy and psychopharmacology.

Clinicians face several challenges when considering antidepressants for pediatric patients. Pediatricians and psychiatrists need to understand whether these medications work in children and adolescents, and whether there are unique developmental safety and tolerability issues. The evidence base in child psychiatry is considerably smaller compared with that of adult psychiatry. From this more limited evidence base also came the controversial “black-box” warning regarding a risk of emergent suicidality when starting antidepressants that accompanies all antidepressants for pediatric, but not adult, patients. This warning has had major effects on clinical encounters with children experiencing depression, including altering clinician prescribing behavior.¹²

In this article, we review the current evidence for antidepressant efficacy, tolerability, and safety in pediatric patients. We also suggest ways in which clinicians might choose, start, and stop antidepressants in children, as well as how to talk with parents about benefits, risks, and the black-box warning.

Do antidepressants work in children?

Selective serotonin reuptake inhibitors. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used class of antidepressants in both children and adults.¹³ While only a few SSRIs are FDA-approved for pediatric indications, the lack of FDA approval is typically related to a lack of sufficient testing in randomized controlled trials (RCTs) for specific pediatric indications, rather than to demonstrable differences in efficacy between antidepressant agents. Since there is currently no data to suggest inferiority of one agent compared to another in children or adults,^14,15 efficacy data will be discussed here as applied to the class of SSRIs, generalizing from RCTs conducted on individual drugs. Table 1 lists FDA indications and dosing information for individual antidepressants.

There is strong evidence that SSRIs are effective for treating pediatric anxiety disorders (eg, social anxiety disorder and GAD)¹⁶ and OCD,¹⁷ with numbers needed to treat (NNT) between 3 and 5. For both of these disorders, SSRIs combined with cognitive-behavioral therapy (CBT) have the highest likelihood of improving symptoms or achieving remission.^17,18

Selective serotonin reuptake inhibitors are also effective for treating pediatric MDD; however, the literature is more complex for this disorder compared to GAD and OCD as there are considerable differences in effect sizes between National Institute of Mental Health (NIMH)–funded studies and industry-sponsored trials.¹³ The major NIMH-sponsored adolescent depression trial, TADS (Treatment for Adolescents and Depression Study), showed that SSRIs (fluoxetine in this case) were quite effective, with an NNT of 4 over the acute phase (12 weeks).¹⁹ Ultimately, approximately 80% of adolescents improved over 9 months. Many industry-sponsored trials for MDD in pediatric patients had large placebo response rates (approximately 60%), which resulted in smaller between-group differences, and estimates of an NNT closer to 12,¹³ which has muddied the waters in meta-analyses that include all trials.²⁰ Improvement in depressive symptoms also appears to be bolstered by concomitant CBT in MDD,¹⁹ but not as robustly as in GAD and OCD. While the full benefit of SSRIs for depression may take as long as 8 weeks, a meta-analysis of depression studies of pediatric patients suggests that significant benefits from placebo are observed as early as 2 weeks, and that further treatment gains are minimal after 4 weeks.¹⁵ Thus, we recommend at least a 4- to 6-week trial at therapeutic dosing before deeming a medication a treatment failure.

Continue to: Posttraumatic stress disorder...

Posttraumatic stress disorder is a fourth disorder in which SSRIs are a first-line treatment in adults. The data for using SSRIs to treat pediatric patients with PTSD is scant, with only a few RCTs, and no large NIMH-funded trials. Randomized controlled trials have not demonstrated significant differences between SSRIs and placebo^21,22 and thus the current first-line recommendation in pediatric PTSD remains trauma-focused therapy, with good evidence for trauma-focused CBT.²³ Practically speaking, there can be considerable overlap of PTSD, depression, and anxiety symptoms in children,²³ and children with a history of trauma who also have comorbid MDD may benefit from medication if their symptoms persist despite an adequate trial of psychotherapy.

Taken together, the current evidence suggests that SSRIs are often effective in pediatric GAD, OCD, and MDD, with low NNTs (ranging from 3 to 5 based on NIMH-funded trials) for all of these disorders; there is not yet sufficient evidence of efficacy in pediatric patients with PTSD.

Fluoxetine has been studied more intensively than other SSRIs (for example, it was the antidepressant used in the TADS trial), and thus has the largest evidence base. For this reason, fluoxetine is often considered the first of the first-line options. Additionally, fluoxetine has a longer half-life than other antidepressants, which may make it more effective in situations where patients are likely to miss doses, and results in a lower risk of withdrawal symptoms when stopped due to “self-tapering.”

SNRIs and atypical antidepressants. Other antidepressants commonly used in pediatric patients but with far less evidence of efficacy include serotonin-norepinephrine reuptake inhibitors (SNRIs) and the atypical antidepressants bupropion and mirtazapine. The SNRI duloxetine is FDA-approved for treating GAD in children age 7 to 17, but there are no other pediatric indications for duloxetine, or for the other SNRIs.

In general, adverse effect profiles are worse for SNRIs compared to SSRIs, further limiting their utility. While there are no pediatric studies demonstrating SNRI efficacy for neuropathic pain, good data exists in adults.²⁴ Thus, an SNRI could be a reasonable option if a pediatric patient has failed prior adequate SSRI trials and also has comorbid neuropathic pain.

Continue to: Neither bupropion nor mirtazapine...

Neither bupropion nor mirtazapine have undergone rigorous testing in pediatric patients, and therefore these agents should generally be considered only once other first-line treatments have failed. Bupropion has been evaluated for attention-deficit/hyperactivity disorder (ADHD)²⁵ and for adolescent smoking cessation.²⁶ However, the evidence is weak, and bupropion is not considered a first-line option for children and adolescents.

Tricyclic antidepressants. Randomized controlled trials have demonstrated that tricyclic antidepressants (TCAs) are efficacious for treating several pediatric conditions; however, their significant side effect profile, their monitoring requirements, as well as their lethality in overdose has left them replaced by SSRIs in most cases. That said, they can be appropriate in refractory ADHD (desipramine^27,28) and refractory OCD (clomipramine is FDA-approved for this indication²⁹); they are considered a third-line treatment for enuresis.³⁰

Why did my patient stop the medication?

Common adverse effects. Although the greatest benefit of antidepressant medications compared with placebo is achieved relatively early on in treatment, it generally takes time for these benefits to accrue and become clinically apparent.^15,31 By contrast, most adverse effects of antidepressants present and are at their most severe early in treatment. The combination of early adverse effects and delayed efficacy leads many patients, families, and clinicians to discontinue medications before they have an adequate chance to work. Thus, it is imperative to provide psychoeducation before starting a medication about the typical time-course of improvement and adverse effects (Table 2).

Adverse effects of SSRIs often appear or worsen transiently during initiation of a medication, during a dose increase,³² or, theoretically, with the addition of a medication that interferes with SSRI metabolism (eg, cimetidine inhibition of cytochrome P450 2D6).³³ If families are prepared for this phenomenon and the therapeutic alliance is adequate, adverse effects can be tolerated to allow for a full medication trial. Common adverse effects of SSRIs include sleep problems (insomnia/sedation), gastrointestinal upset, sexual dysfunction, dry mouth, and hyperhidrosis. Although SSRIs differ somewhat in the frequency of these effects, as a class, they are more similar than different. Adequate psychoeducation is especially imperative in the treatment of OCD and anxiety disorders, where there is limited evidence of efficacy for any non-serotonergic antidepressants.

Serotonin-norepinephrine reuptake inhibitors are not considered first-line medications because of the reduced evidence base compared to SSRIs and their enhanced adverse effect profiles. Because SNRIs partially share a mechanism of action with SSRIs, they also share portions of the adverse effects profile. However, SNRIs have the additional adverse effect of hypertension, which is related to their noradrenergic activity. Thus, it is reasonable to obtain a baseline blood pressure before initiating an SNRI, as well as periodically after initiation and during dose increases, particularly if the patient has other risk factors for hypertension.³⁴

Continue to: Although TCAs have efficacy...

Although TCAs have efficacy in some pediatric disorders,^27-29,35 their adverse effect profile limits their use. Tricyclic antidepressants are highly anticholinergic (causing dizziness secondary to orthostatic hypotension, dry mouth, and urinary retention) and antihistaminergic (causing sedation and weight gain). Additionally, TCAs lower the seizure threshold and have adverse cardiac effects relating to their anti-alpha-1 adrenergic activity, resulting in dose-dependent increases in the QTc and cardiac toxicity in overdose that could lead to arrhythmia and death. These medications have their place, but their use requires careful informed consent, clear treatment goals, and baseline and periodic cardiac monitoring (via electrocardiogram).

Serious adverse effects. Clinicians may be hesitant to prescribe antidepressants for pediatric patients because of the potential for more serious adverse effects, including severe behavioral activation syndromes, serotonin syndrome, and emergent suicidality. However, current FDA-approved antidepressants arguably have one of the most positive risk/benefit profiles of any orally-administered medication approved for pediatric patients. Having a strong understanding of the evidence is critical to evaluating when it is appropriate to prescribe an antidepressant, how to properly monitor the patient, and how to obtain accurate informed consent.

Pediatric behavioral activation syndrome. Many clinicians report that children receiving antidepressants experience a pediatric behavioral activation syndrome, which exists along a spectrum from mild activation, increased energy, insomnia, or irritability up through more severe presentations of agitation, hyperactivity, or possibly mania. A recent meta-analysis suggested a positive association between antidepressant use and activation events on the milder end of this spectrum in pediatric patients with non-OCD anxiety disorders,¹⁶ and it is thought that compared with adolescents, younger children are more susceptible to activation adverse effects.³⁶ The likelihood of activation events has been associated with higher antidepressant plasma levels,³⁷ suggesting that dose or individual differences in metabolism may play a role. At the severe end of the spectrum, the risk of induction of mania in pediatric patients with depression or anxiety is relatively rare (<2%) and not statistically different from placebo in RCTs of pediatric participants.³⁸ Meta-analyses of larger randomized, placebo-controlled trials of adults do not support the idea that SSRIs and other second-generation antidepressants carry an increased risk of mania compared with placebo.^39,40 Children or adolescents with bona fide bipolar disorder (ie, patients who have had observed mania that meets all DSM-5 criteria) should be treated with a mood-stabilizing agent or antipsychotic if prescribed an antidepressant.⁴¹ These clear-cut cases are, however, relatively rare, and more often clinicians are confronted with ambiguous cases that include a family history of bipolar disorder along with “softer” symptoms of irritability, intrusiveness, or aggression. In these children, SSRIs may be appropriate for depressive, OCD, or anxiety symptoms, and should be strongly considered before prescribing antipsychotics or mood stabilizers, as long as initiated with proper monitoring.

Serotonin syndrome is a life-threatening condition caused by excess synaptic serotonin. It is characterized by confusion, sweating, diarrhea, hypertension, hyperthermia, and tachycardia. At its most severe, serotonin syndrome can result in seizures, arrhythmias, and death. The risk of serotonin syndrome is very low when using an SSRI as monotherapy. Risk increases with polypharmacy, particularly unexamined polypharmacy when multiple serotonergic agents are inadvertently on board. Commonly used serotonergic agents include other antidepressants, migraine medications (eg, triptans), some pain medications, and the cough suppressant dextromethorphan.

The easiest way to mitigate the risk of serotonin syndrome is to use an interaction index computer program, which can help ensure that the interacting agents are not prescribed without first discussing the risks and benefits. It is important to teach adolescents that certain recreational drugs are highly serotonergic and can cause serious interactions with antidepressants. For example, recreational use of dextrometh­orphan or 3,4-methylenedioxymethamphetamine (MDMA; commonly known as “ecstasy”) has been associated with serotonin syndrome in adolescents taking antidepressant medications.^42,43

Continue to: Suicidality

Suicidality. The black-box warning regarding a risk of emergent suicidality when starting antidepressant treatment in children is controversial.⁴⁴ The prospect that a medication intended to ameliorate depression might instead risk increasing suicidal thinking is alarming to parents and clinicians alike. To appropriately weigh and discuss the risks and benefits with families, it is important to understand the data upon which the warning is based.

In 2004, the FDA commissioned a review of 23 antidepressant trials, both published and unpublished, pooling studies across multiple indications (MDD, OCD, anxiety, and ADHD) and multiple antidepressant classes. This meta-analysis, which included nearly 4,400 pediatric patients, found a small but statistically significant increase in spontaneously-reported suicidal thoughts or actions, with a risk difference of 1% (95% confidence interval [CI], 1% to 2%).⁴⁵ These data suggest that if one treats 100 pediatric patients, 1 to 2 of them may experience short-term increases in suicidal thinking or behavior.⁴⁵ There were no differences in suicidal thinking when assessed systematically (ie, when all subjects reported symptoms of suicidal ideation on structured rating scales), and there were no completed suicides.⁴⁵ A subsequent analysis that included 27 pediatric trials suggested an even lower, although still significant, risk difference (<1%), yielding a number needed to harm (NNH) of 143.⁴⁶ Thus, with low NNT for efficacy (3 to 6) and relatively high NNH for emergent suicidal thoughts or behaviors (100 to 143), for many patients the benefits will outweigh the risks.

Figure 1, Figure 2, and Figure 3 are Cates plots that depict the absolute benefits of antidepressants compared with the risk of suicidality for pediatric patients with MDD, OCD, and anxiety disorders. Recent meta-analyses have suggested that the increased risk of suicidality in antidepressant trials is specific to studies that included children and adolescents, and is not observed in adult studies. A meta-analysis of 70 trials involving 18,526 participants suggested that the odds ratio of suicidality in trials of children and adolescents was 2.39 (95% CI, 1.31 to 4.33) compared with 0.81 (95% CI, 0.51 to 1.28) in adults.⁴⁷ Additionally, a network meta-analysis exclusively focusing on pediatric antidepressant trials in MDD reported significantly higher suicidality-related adverse events in venlafaxine trials compared with placebo, duloxetine, and several SSRIs (fluoxetine, paroxetine, and escitalopram).²⁰ These data should be interpreted with caution as differences in suicidality detected between agents is quite possibly related to differences in the method of assessment between trials, as opposed to actual differences in risk between agents.

Epidemiologic data further support the use of antidepressants in pediatric patients, showing that antidepressant use is associated with decreased teen suicide attempts and completions,⁴⁸ and the decline in prescriptions that occurred following the black-box warning was accompanied by a 14% increase in teen suicides.⁴⁹ Multiple hypotheses have been proposed to explain the pediatric clinical trial findings. One idea is that potential adverse effects of activation, or the intended effects of restoring the motivation, energy, and social engagement that is often impaired in depression, increases the likelihood of thinking about suicide or acting on thoughts. Another theory is that reporting of suicidality may be increased, rather than increased de novo suicidality itself. Antidepressants are effective for treating pediatric anxiety disorders, including social anxiety disorder,¹⁶ which could result in more willingness to report. Also, the manner in which adverse effects are generally ascertained in trials might have led to increased spontaneous reporting. In many trials, investigators ask whether participants have any adverse effects in general, and inquire about specific adverse effects only if the family answers affirmatively. Thus, the increased rate of other adverse effects associated with antidepressants (sleep problems, gastrointestinal upset, dry mouth, etc.) might trigger a specific question regarding suicidal ideation, which the child or family then may be more likely to report. Alternatively, any type of psychiatric treatment could increase an individual’s propensity to report; in adolescent psychotherapy trials, non-medicated participants have reported emergent suicidality at similar frequencies as those described in drug trials.⁵⁰ Regardless of the mechanism, the possibility of treatment-emergent suicidality is a low-frequency but serious event that necessitates careful monitoring when starting medication. Current guidelines suggest seeing children weekly for the first month after medication initiation, every 2 weeks for the following month, and monthly thereafter.⁵¹

Continue to: How long should the antidepressant be continued?

How long should the antidepressant be continued?

Many patients are concerned about how long they may be taking medication, and whether they will be taking an antidepressant “forever.” A treatment course can be broken into an acute phase, wherein remission is achieved and maintained for 6 to 8 weeks. This is followed by a continuation phase, with the goal of relapse prevention, lasting 16 to 20 weeks. The length of the last phase—the maintenance phase—depends both on the child’s history, the underlying therapeutic indication, the adverse effect burden experienced, and the family’s preferences/values. In general, for a first depressive episode, after treating for 1 year, a trial of discontinuation can be attempted with close monitoring. For a second depressive episode, we recommend 2 years of remission on antidepressant therapy before attempting discontinuation. In patients who have had 3 depressive episodes, or have had episodes of high severity, we recommend continuing antidepressant treatment indefinitely. Although much less well studied, the risk of relapse following SSRI discontinuation appears much more significant in OCD, whereas anxiety disorders and MDD have a relatively comparable risk.⁵²

In general, stopping an antidepressant should be done carefully and slowly. The speed with which a specific antidepressant can be stopped is largely related to its half-life. Agents with very long half-lives, such as fluoxetine (half-life of 5 days for the parent compound and 9 days for active metabolite), can often be stopped altogether, being “auto-tapered” by the long half-life. One might still consider a taper if the patient were taking high doses. Medications with shorter half-lives must be more carefully tapered to avoid discontinuation syndromes. Discontinuation syndromes are characterized by flu-like symptoms (nausea, myalgias, fatigue, dizziness) and worsening mood. Medications with short half-lives (eg, paroxetine and venlafaxine) have the highest potential for this syndrome in children,⁵³ and thus are used less frequently.

What to do when first-line treatments fail

When a child does not experience sufficient improvement from first-line treatments, it is crucial to determine whether they have experienced an adequate dosing, duration, and quality of medication and psychotherapy.

Adequate psychotherapy? To determine whether children are receiving adequate CBT, ask:

1. if the child receives homework from psychotherapy
2. if the parents are included in treatment
3. if therapy has involved identifying thought patterns that may be contributing to the child’s illness, and
4. if the therapist has ever exposed the child to a challenge likely to produce anxiety or distress in a supervised environment and has developed an exposure hierarchy (for conditions with primarily exposure-based therapies, such as OCD or anxiety disorders).

If a family is not receiving most of these elements in psychotherapy, this is a good indicator that they may not be receiving evidence-based CBT.

Continue to: Adequate pharmacotherapy?

Adequate pharmacotherapy? Similarly, when determining the adequacy of previous pharmacotherapy, it is critical to determine whether the child received an adequate dose of medications (at least the FDA-recommended minimum dose) for an adequate duration of time at therapeutic dosing (at least 6 weeks for MDD, 8 weeks for anxiety disorders, and 8 to 12 weeks for pediatric patients with OCD), and that the child actually took the medication regularly during that period. Patient compliance can typically be tracked through checking refill requests or intervals through the patient’s pharmacy. Ensuring proper delivery of first-line treatments is imperative because (1) the adverse effects associated with second-line treatments are often more substantial; (2) the cost in terms of time and money is considerably higher with second-line treatments, and; (3) the evidence regarding the benefits of these treatments is much less certain.

Inadequate dosing is a common reason for non-response in pediatric patients. Therapeutic dose ranges for common antidepressants are displayed in Table 1. Many clinicians underdose antidepressants for pediatric patients initially (and often throughout treatment) because they fear that the typical dose titration used in clinical trials will increase the risk of adverse effects compared with more conservative dosing. There is limited evidence to suggest that this underdosing strategy is likely to be successful; adverse effects attributable to these medications are modest, and most that are experienced early in treatment (eg, headache, increased anxiety or irritability, sleep problems, gastrointestinal upset) are self-limiting and may be coincidental rather than medication-induced. Furthermore, there is no evidence for efficacy of subtherapeutic dosing in children in the acute phase of treatment or for preventing relapse.¹⁴ Thus, from an efficacy standpoint, a medication trial has not officially begun until the therapeutic dose range is reached.

Once dosing is within the therapeutic range, however, pediatric data differs from the adult literature. In most adult psychi­atric conditions, higher doses of SSRIs within the therapeutic range are associated with an increased response rate.^14,54 In pediatrics, there are few fixed dose trials, and once within the recommended therapeutic range, minimal data supports an association between higher dosing and higher efficacy.¹⁴ In general, pediatric guidelines are silent regarding optimal dosing of SSRIs within the recommended dose range, and higher antidepressant doses often result in a more significant adverse effect burden for children. One exception is pediatric OCD, where, similar to adults, the guidelines suggest that higher dosing of SSRIs often is required to induce a therapeutic response as compared to MDD and GAD.^31,55

If a child does not respond to adequate first-line treatment (or has a treatment history that cannot be fully verified), repeating these first-line interventions carries little risk and can be quite effective. For example, 60% of adolescents with MDD who did not initially respond to an SSRI demonstrated a significant response when prescribed a second SSRI or venlafaxine (with or without CBT).⁵⁶

When pediatric patients continue to experience significantly distressing and/or debilitating symptoms (particularly in MDD) despite multiple trials of antidepressants and psychotherapy, practitioners should consider a careful referral to interventional psychiatry services, which can include the more intensive treatments of electroconvulsive therapy, repetitive transcranial magnetic stimulation, or ketamine (see Box 1). Given the substantial morbidity and mortality associated with adolescent depression, interventional psychiatry treatments are under-researched and under-utilized clinically in pediatric populations.

Continue to: Antidepressants in general...

Antidepressants in general, and SSRIs in particular, are the first-line pharmacotherapy for pediatric anxiety, OCD, and MDD. For PTSD, although they are a first-line treatment in adults, their efficacy has not been demonstrated in children and adolescents. Antidepressants are generally safe, well-tolerated, and effective, with low NNTs (3 to 5 for anxiety and OCD; 4 to 12 in MDD, depending on whether industry trials are included). It is important that clinicians and families be educated about possible adverse effects and their time course in order to anticipate difficulties, ensure adequate informed consent, and monitor appropriately. The black-box warning regarding treatment-emergent suicidal thoughts or behaviors must be discussed (for suggested talking points, see Box 2). The NNH is large (100 to 143), and for many patients, the benefits will outweigh the risks. For pediatric patients who fail to respond to multiple adequate trials of antidepressants and psychotherapy, referrals for interventional psychiatry consultation should be considered.

Bottom Line

Although the evidence base for prescribing antidepressants for children and adolescents is smaller compared to the adult literature, properly understanding and prescribing these agents, and explaining their risks and benefits to families, can make a major difference in patient compliance, satisfaction, and outcomes. Antidepressants (particularly selective serotonin reuptake inhibitors) are the firstline pharmacologic intervention for pediatric patients with anxiety disorders, obsessive-compulsive disorder, or major depressive disorder.

Related Resource

• Bonin L, Moreland CS. Overview of prevention and treatment for pediatric depression. https://www.uptodate.com/contents/overview-of-prevention-and-treatment-for-pediatric-depression. Last reviewed July 2019.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Cimetidine • Tagamet
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fluvoxamine • Luvox
Imipramine • Tofranil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor
Vilazodone • Viibryd
Vortioxetine • Trintellix

Box 1

Box 2

Major depressive disorder (MDD) is a significant pediatric health problem, with a lifetime prevalence as high as 20% by the end of adolescence.^1-3 Major depressive disorder in adolescence is associated with significant morbidity, including poor social functioning, school difficulties, early pregnancy, and increased risk of physical illness and substance abuse.^4-6 It is also linked with significant mortality, with increased risk for suicide, which is now the second leading cause of death in individuals age 10 to 24 years.^1,7,8

As their name suggests, antidepressants comprise a group of medications that are used to treat MDD; they are also, however, first-line agents for generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD) in adults. Anxiety disorders (including GAD and other anxiety diagnoses) and PTSD are also common in childhood and adolescence with a combined lifetime prevalence ranging from 15% to 30%.^9,10 These disorders are also associated with increased risk of suicide.¹¹ For all of these disorders, depending on the severity of presentation and the preference of the patient, treatments are often a combination of psychotherapy and psychopharmacology.

Clinicians face several challenges when considering antidepressants for pediatric patients. Pediatricians and psychiatrists need to understand whether these medications work in children and adolescents, and whether there are unique developmental safety and tolerability issues. The evidence base in child psychiatry is considerably smaller compared with that of adult psychiatry. From this more limited evidence base also came the controversial “black-box” warning regarding a risk of emergent suicidality when starting antidepressants that accompanies all antidepressants for pediatric, but not adult, patients. This warning has had major effects on clinical encounters with children experiencing depression, including altering clinician prescribing behavior.¹²

In this article, we review the current evidence for antidepressant efficacy, tolerability, and safety in pediatric patients. We also suggest ways in which clinicians might choose, start, and stop antidepressants in children, as well as how to talk with parents about benefits, risks, and the black-box warning.

Do antidepressants work in children?

Selective serotonin reuptake inhibitors. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used class of antidepressants in both children and adults.¹³ While only a few SSRIs are FDA-approved for pediatric indications, the lack of FDA approval is typically related to a lack of sufficient testing in randomized controlled trials (RCTs) for specific pediatric indications, rather than to demonstrable differences in efficacy between antidepressant agents. Since there is currently no data to suggest inferiority of one agent compared to another in children or adults,^14,15 efficacy data will be discussed here as applied to the class of SSRIs, generalizing from RCTs conducted on individual drugs. Table 1 lists FDA indications and dosing information for individual antidepressants.

There is strong evidence that SSRIs are effective for treating pediatric anxiety disorders (eg, social anxiety disorder and GAD)¹⁶ and OCD,¹⁷ with numbers needed to treat (NNT) between 3 and 5. For both of these disorders, SSRIs combined with cognitive-behavioral therapy (CBT) have the highest likelihood of improving symptoms or achieving remission.^17,18

Selective serotonin reuptake inhibitors are also effective for treating pediatric MDD; however, the literature is more complex for this disorder compared to GAD and OCD as there are considerable differences in effect sizes between National Institute of Mental Health (NIMH)–funded studies and industry-sponsored trials.¹³ The major NIMH-sponsored adolescent depression trial, TADS (Treatment for Adolescents and Depression Study), showed that SSRIs (fluoxetine in this case) were quite effective, with an NNT of 4 over the acute phase (12 weeks).¹⁹ Ultimately, approximately 80% of adolescents improved over 9 months. Many industry-sponsored trials for MDD in pediatric patients had large placebo response rates (approximately 60%), which resulted in smaller between-group differences, and estimates of an NNT closer to 12,¹³ which has muddied the waters in meta-analyses that include all trials.²⁰ Improvement in depressive symptoms also appears to be bolstered by concomitant CBT in MDD,¹⁹ but not as robustly as in GAD and OCD. While the full benefit of SSRIs for depression may take as long as 8 weeks, a meta-analysis of depression studies of pediatric patients suggests that significant benefits from placebo are observed as early as 2 weeks, and that further treatment gains are minimal after 4 weeks.¹⁵ Thus, we recommend at least a 4- to 6-week trial at therapeutic dosing before deeming a medication a treatment failure.

Continue to: Posttraumatic stress disorder...

Posttraumatic stress disorder is a fourth disorder in which SSRIs are a first-line treatment in adults. The data for using SSRIs to treat pediatric patients with PTSD is scant, with only a few RCTs, and no large NIMH-funded trials. Randomized controlled trials have not demonstrated significant differences between SSRIs and placebo^21,22 and thus the current first-line recommendation in pediatric PTSD remains trauma-focused therapy, with good evidence for trauma-focused CBT.²³ Practically speaking, there can be considerable overlap of PTSD, depression, and anxiety symptoms in children,²³ and children with a history of trauma who also have comorbid MDD may benefit from medication if their symptoms persist despite an adequate trial of psychotherapy.

Taken together, the current evidence suggests that SSRIs are often effective in pediatric GAD, OCD, and MDD, with low NNTs (ranging from 3 to 5 based on NIMH-funded trials) for all of these disorders; there is not yet sufficient evidence of efficacy in pediatric patients with PTSD.

Fluoxetine has been studied more intensively than other SSRIs (for example, it was the antidepressant used in the TADS trial), and thus has the largest evidence base. For this reason, fluoxetine is often considered the first of the first-line options. Additionally, fluoxetine has a longer half-life than other antidepressants, which may make it more effective in situations where patients are likely to miss doses, and results in a lower risk of withdrawal symptoms when stopped due to “self-tapering.”

SNRIs and atypical antidepressants. Other antidepressants commonly used in pediatric patients but with far less evidence of efficacy include serotonin-norepinephrine reuptake inhibitors (SNRIs) and the atypical antidepressants bupropion and mirtazapine. The SNRI duloxetine is FDA-approved for treating GAD in children age 7 to 17, but there are no other pediatric indications for duloxetine, or for the other SNRIs.

In general, adverse effect profiles are worse for SNRIs compared to SSRIs, further limiting their utility. While there are no pediatric studies demonstrating SNRI efficacy for neuropathic pain, good data exists in adults.²⁴ Thus, an SNRI could be a reasonable option if a pediatric patient has failed prior adequate SSRI trials and also has comorbid neuropathic pain.

Continue to: Neither bupropion nor mirtazapine...

Neither bupropion nor mirtazapine have undergone rigorous testing in pediatric patients, and therefore these agents should generally be considered only once other first-line treatments have failed. Bupropion has been evaluated for attention-deficit/hyperactivity disorder (ADHD)²⁵ and for adolescent smoking cessation.²⁶ However, the evidence is weak, and bupropion is not considered a first-line option for children and adolescents.

Tricyclic antidepressants. Randomized controlled trials have demonstrated that tricyclic antidepressants (TCAs) are efficacious for treating several pediatric conditions; however, their significant side effect profile, their monitoring requirements, as well as their lethality in overdose has left them replaced by SSRIs in most cases. That said, they can be appropriate in refractory ADHD (desipramine^27,28) and refractory OCD (clomipramine is FDA-approved for this indication²⁹); they are considered a third-line treatment for enuresis.³⁰

Why did my patient stop the medication?

Common adverse effects. Although the greatest benefit of antidepressant medications compared with placebo is achieved relatively early on in treatment, it generally takes time for these benefits to accrue and become clinically apparent.^15,31 By contrast, most adverse effects of antidepressants present and are at their most severe early in treatment. The combination of early adverse effects and delayed efficacy leads many patients, families, and clinicians to discontinue medications before they have an adequate chance to work. Thus, it is imperative to provide psychoeducation before starting a medication about the typical time-course of improvement and adverse effects (Table 2).

Adverse effects of SSRIs often appear or worsen transiently during initiation of a medication, during a dose increase,³² or, theoretically, with the addition of a medication that interferes with SSRI metabolism (eg, cimetidine inhibition of cytochrome P450 2D6).³³ If families are prepared for this phenomenon and the therapeutic alliance is adequate, adverse effects can be tolerated to allow for a full medication trial. Common adverse effects of SSRIs include sleep problems (insomnia/sedation), gastrointestinal upset, sexual dysfunction, dry mouth, and hyperhidrosis. Although SSRIs differ somewhat in the frequency of these effects, as a class, they are more similar than different. Adequate psychoeducation is especially imperative in the treatment of OCD and anxiety disorders, where there is limited evidence of efficacy for any non-serotonergic antidepressants.

Serotonin-norepinephrine reuptake inhibitors are not considered first-line medications because of the reduced evidence base compared to SSRIs and their enhanced adverse effect profiles. Because SNRIs partially share a mechanism of action with SSRIs, they also share portions of the adverse effects profile. However, SNRIs have the additional adverse effect of hypertension, which is related to their noradrenergic activity. Thus, it is reasonable to obtain a baseline blood pressure before initiating an SNRI, as well as periodically after initiation and during dose increases, particularly if the patient has other risk factors for hypertension.³⁴

Continue to: Although TCAs have efficacy...

Although TCAs have efficacy in some pediatric disorders,^27-29,35 their adverse effect profile limits their use. Tricyclic antidepressants are highly anticholinergic (causing dizziness secondary to orthostatic hypotension, dry mouth, and urinary retention) and antihistaminergic (causing sedation and weight gain). Additionally, TCAs lower the seizure threshold and have adverse cardiac effects relating to their anti-alpha-1 adrenergic activity, resulting in dose-dependent increases in the QTc and cardiac toxicity in overdose that could lead to arrhythmia and death. These medications have their place, but their use requires careful informed consent, clear treatment goals, and baseline and periodic cardiac monitoring (via electrocardiogram).

Serious adverse effects. Clinicians may be hesitant to prescribe antidepressants for pediatric patients because of the potential for more serious adverse effects, including severe behavioral activation syndromes, serotonin syndrome, and emergent suicidality. However, current FDA-approved antidepressants arguably have one of the most positive risk/benefit profiles of any orally-administered medication approved for pediatric patients. Having a strong understanding of the evidence is critical to evaluating when it is appropriate to prescribe an antidepressant, how to properly monitor the patient, and how to obtain accurate informed consent.

Pediatric behavioral activation syndrome. Many clinicians report that children receiving antidepressants experience a pediatric behavioral activation syndrome, which exists along a spectrum from mild activation, increased energy, insomnia, or irritability up through more severe presentations of agitation, hyperactivity, or possibly mania. A recent meta-analysis suggested a positive association between antidepressant use and activation events on the milder end of this spectrum in pediatric patients with non-OCD anxiety disorders,¹⁶ and it is thought that compared with adolescents, younger children are more susceptible to activation adverse effects.³⁶ The likelihood of activation events has been associated with higher antidepressant plasma levels,³⁷ suggesting that dose or individual differences in metabolism may play a role. At the severe end of the spectrum, the risk of induction of mania in pediatric patients with depression or anxiety is relatively rare (<2%) and not statistically different from placebo in RCTs of pediatric participants.³⁸ Meta-analyses of larger randomized, placebo-controlled trials of adults do not support the idea that SSRIs and other second-generation antidepressants carry an increased risk of mania compared with placebo.^39,40 Children or adolescents with bona fide bipolar disorder (ie, patients who have had observed mania that meets all DSM-5 criteria) should be treated with a mood-stabilizing agent or antipsychotic if prescribed an antidepressant.⁴¹ These clear-cut cases are, however, relatively rare, and more often clinicians are confronted with ambiguous cases that include a family history of bipolar disorder along with “softer” symptoms of irritability, intrusiveness, or aggression. In these children, SSRIs may be appropriate for depressive, OCD, or anxiety symptoms, and should be strongly considered before prescribing antipsychotics or mood stabilizers, as long as initiated with proper monitoring.

Serotonin syndrome is a life-threatening condition caused by excess synaptic serotonin. It is characterized by confusion, sweating, diarrhea, hypertension, hyperthermia, and tachycardia. At its most severe, serotonin syndrome can result in seizures, arrhythmias, and death. The risk of serotonin syndrome is very low when using an SSRI as monotherapy. Risk increases with polypharmacy, particularly unexamined polypharmacy when multiple serotonergic agents are inadvertently on board. Commonly used serotonergic agents include other antidepressants, migraine medications (eg, triptans), some pain medications, and the cough suppressant dextromethorphan.

The easiest way to mitigate the risk of serotonin syndrome is to use an interaction index computer program, which can help ensure that the interacting agents are not prescribed without first discussing the risks and benefits. It is important to teach adolescents that certain recreational drugs are highly serotonergic and can cause serious interactions with antidepressants. For example, recreational use of dextrometh­orphan or 3,4-methylenedioxymethamphetamine (MDMA; commonly known as “ecstasy”) has been associated with serotonin syndrome in adolescents taking antidepressant medications.^42,43

Continue to: Suicidality

Suicidality. The black-box warning regarding a risk of emergent suicidality when starting antidepressant treatment in children is controversial.⁴⁴ The prospect that a medication intended to ameliorate depression might instead risk increasing suicidal thinking is alarming to parents and clinicians alike. To appropriately weigh and discuss the risks and benefits with families, it is important to understand the data upon which the warning is based.

In 2004, the FDA commissioned a review of 23 antidepressant trials, both published and unpublished, pooling studies across multiple indications (MDD, OCD, anxiety, and ADHD) and multiple antidepressant classes. This meta-analysis, which included nearly 4,400 pediatric patients, found a small but statistically significant increase in spontaneously-reported suicidal thoughts or actions, with a risk difference of 1% (95% confidence interval [CI], 1% to 2%).⁴⁵ These data suggest that if one treats 100 pediatric patients, 1 to 2 of them may experience short-term increases in suicidal thinking or behavior.⁴⁵ There were no differences in suicidal thinking when assessed systematically (ie, when all subjects reported symptoms of suicidal ideation on structured rating scales), and there were no completed suicides.⁴⁵ A subsequent analysis that included 27 pediatric trials suggested an even lower, although still significant, risk difference (<1%), yielding a number needed to harm (NNH) of 143.⁴⁶ Thus, with low NNT for efficacy (3 to 6) and relatively high NNH for emergent suicidal thoughts or behaviors (100 to 143), for many patients the benefits will outweigh the risks.

Figure 1, Figure 2, and Figure 3 are Cates plots that depict the absolute benefits of antidepressants compared with the risk of suicidality for pediatric patients with MDD, OCD, and anxiety disorders. Recent meta-analyses have suggested that the increased risk of suicidality in antidepressant trials is specific to studies that included children and adolescents, and is not observed in adult studies. A meta-analysis of 70 trials involving 18,526 participants suggested that the odds ratio of suicidality in trials of children and adolescents was 2.39 (95% CI, 1.31 to 4.33) compared with 0.81 (95% CI, 0.51 to 1.28) in adults.⁴⁷ Additionally, a network meta-analysis exclusively focusing on pediatric antidepressant trials in MDD reported significantly higher suicidality-related adverse events in venlafaxine trials compared with placebo, duloxetine, and several SSRIs (fluoxetine, paroxetine, and escitalopram).²⁰ These data should be interpreted with caution as differences in suicidality detected between agents is quite possibly related to differences in the method of assessment between trials, as opposed to actual differences in risk between agents.

Epidemiologic data further support the use of antidepressants in pediatric patients, showing that antidepressant use is associated with decreased teen suicide attempts and completions,⁴⁸ and the decline in prescriptions that occurred following the black-box warning was accompanied by a 14% increase in teen suicides.⁴⁹ Multiple hypotheses have been proposed to explain the pediatric clinical trial findings. One idea is that potential adverse effects of activation, or the intended effects of restoring the motivation, energy, and social engagement that is often impaired in depression, increases the likelihood of thinking about suicide or acting on thoughts. Another theory is that reporting of suicidality may be increased, rather than increased de novo suicidality itself. Antidepressants are effective for treating pediatric anxiety disorders, including social anxiety disorder,¹⁶ which could result in more willingness to report. Also, the manner in which adverse effects are generally ascertained in trials might have led to increased spontaneous reporting. In many trials, investigators ask whether participants have any adverse effects in general, and inquire about specific adverse effects only if the family answers affirmatively. Thus, the increased rate of other adverse effects associated with antidepressants (sleep problems, gastrointestinal upset, dry mouth, etc.) might trigger a specific question regarding suicidal ideation, which the child or family then may be more likely to report. Alternatively, any type of psychiatric treatment could increase an individual’s propensity to report; in adolescent psychotherapy trials, non-medicated participants have reported emergent suicidality at similar frequencies as those described in drug trials.⁵⁰ Regardless of the mechanism, the possibility of treatment-emergent suicidality is a low-frequency but serious event that necessitates careful monitoring when starting medication. Current guidelines suggest seeing children weekly for the first month after medication initiation, every 2 weeks for the following month, and monthly thereafter.⁵¹

Continue to: How long should the antidepressant be continued?

How long should the antidepressant be continued?

Many patients are concerned about how long they may be taking medication, and whether they will be taking an antidepressant “forever.” A treatment course can be broken into an acute phase, wherein remission is achieved and maintained for 6 to 8 weeks. This is followed by a continuation phase, with the goal of relapse prevention, lasting 16 to 20 weeks. The length of the last phase—the maintenance phase—depends both on the child’s history, the underlying therapeutic indication, the adverse effect burden experienced, and the family’s preferences/values. In general, for a first depressive episode, after treating for 1 year, a trial of discontinuation can be attempted with close monitoring. For a second depressive episode, we recommend 2 years of remission on antidepressant therapy before attempting discontinuation. In patients who have had 3 depressive episodes, or have had episodes of high severity, we recommend continuing antidepressant treatment indefinitely. Although much less well studied, the risk of relapse following SSRI discontinuation appears much more significant in OCD, whereas anxiety disorders and MDD have a relatively comparable risk.⁵²

In general, stopping an antidepressant should be done carefully and slowly. The speed with which a specific antidepressant can be stopped is largely related to its half-life. Agents with very long half-lives, such as fluoxetine (half-life of 5 days for the parent compound and 9 days for active metabolite), can often be stopped altogether, being “auto-tapered” by the long half-life. One might still consider a taper if the patient were taking high doses. Medications with shorter half-lives must be more carefully tapered to avoid discontinuation syndromes. Discontinuation syndromes are characterized by flu-like symptoms (nausea, myalgias, fatigue, dizziness) and worsening mood. Medications with short half-lives (eg, paroxetine and venlafaxine) have the highest potential for this syndrome in children,⁵³ and thus are used less frequently.

What to do when first-line treatments fail

When a child does not experience sufficient improvement from first-line treatments, it is crucial to determine whether they have experienced an adequate dosing, duration, and quality of medication and psychotherapy.

Adequate psychotherapy? To determine whether children are receiving adequate CBT, ask:

1. if the child receives homework from psychotherapy
2. if the parents are included in treatment
3. if therapy has involved identifying thought patterns that may be contributing to the child’s illness, and
4. if the therapist has ever exposed the child to a challenge likely to produce anxiety or distress in a supervised environment and has developed an exposure hierarchy (for conditions with primarily exposure-based therapies, such as OCD or anxiety disorders).

If a family is not receiving most of these elements in psychotherapy, this is a good indicator that they may not be receiving evidence-based CBT.

Continue to: Adequate pharmacotherapy?

Adequate pharmacotherapy? Similarly, when determining the adequacy of previous pharmacotherapy, it is critical to determine whether the child received an adequate dose of medications (at least the FDA-recommended minimum dose) for an adequate duration of time at therapeutic dosing (at least 6 weeks for MDD, 8 weeks for anxiety disorders, and 8 to 12 weeks for pediatric patients with OCD), and that the child actually took the medication regularly during that period. Patient compliance can typically be tracked through checking refill requests or intervals through the patient’s pharmacy. Ensuring proper delivery of first-line treatments is imperative because (1) the adverse effects associated with second-line treatments are often more substantial; (2) the cost in terms of time and money is considerably higher with second-line treatments, and; (3) the evidence regarding the benefits of these treatments is much less certain.

Inadequate dosing is a common reason for non-response in pediatric patients. Therapeutic dose ranges for common antidepressants are displayed in Table 1. Many clinicians underdose antidepressants for pediatric patients initially (and often throughout treatment) because they fear that the typical dose titration used in clinical trials will increase the risk of adverse effects compared with more conservative dosing. There is limited evidence to suggest that this underdosing strategy is likely to be successful; adverse effects attributable to these medications are modest, and most that are experienced early in treatment (eg, headache, increased anxiety or irritability, sleep problems, gastrointestinal upset) are self-limiting and may be coincidental rather than medication-induced. Furthermore, there is no evidence for efficacy of subtherapeutic dosing in children in the acute phase of treatment or for preventing relapse.¹⁴ Thus, from an efficacy standpoint, a medication trial has not officially begun until the therapeutic dose range is reached.

Once dosing is within the therapeutic range, however, pediatric data differs from the adult literature. In most adult psychi­atric conditions, higher doses of SSRIs within the therapeutic range are associated with an increased response rate.^14,54 In pediatrics, there are few fixed dose trials, and once within the recommended therapeutic range, minimal data supports an association between higher dosing and higher efficacy.¹⁴ In general, pediatric guidelines are silent regarding optimal dosing of SSRIs within the recommended dose range, and higher antidepressant doses often result in a more significant adverse effect burden for children. One exception is pediatric OCD, where, similar to adults, the guidelines suggest that higher dosing of SSRIs often is required to induce a therapeutic response as compared to MDD and GAD.^31,55

If a child does not respond to adequate first-line treatment (or has a treatment history that cannot be fully verified), repeating these first-line interventions carries little risk and can be quite effective. For example, 60% of adolescents with MDD who did not initially respond to an SSRI demonstrated a significant response when prescribed a second SSRI or venlafaxine (with or without CBT).⁵⁶

When pediatric patients continue to experience significantly distressing and/or debilitating symptoms (particularly in MDD) despite multiple trials of antidepressants and psychotherapy, practitioners should consider a careful referral to interventional psychiatry services, which can include the more intensive treatments of electroconvulsive therapy, repetitive transcranial magnetic stimulation, or ketamine (see Box 1). Given the substantial morbidity and mortality associated with adolescent depression, interventional psychiatry treatments are under-researched and under-utilized clinically in pediatric populations.

Continue to: Antidepressants in general...

Antidepressants in general, and SSRIs in particular, are the first-line pharmacotherapy for pediatric anxiety, OCD, and MDD. For PTSD, although they are a first-line treatment in adults, their efficacy has not been demonstrated in children and adolescents. Antidepressants are generally safe, well-tolerated, and effective, with low NNTs (3 to 5 for anxiety and OCD; 4 to 12 in MDD, depending on whether industry trials are included). It is important that clinicians and families be educated about possible adverse effects and their time course in order to anticipate difficulties, ensure adequate informed consent, and monitor appropriately. The black-box warning regarding treatment-emergent suicidal thoughts or behaviors must be discussed (for suggested talking points, see Box 2). The NNH is large (100 to 143), and for many patients, the benefits will outweigh the risks. For pediatric patients who fail to respond to multiple adequate trials of antidepressants and psychotherapy, referrals for interventional psychiatry consultation should be considered.

Bottom Line

Although the evidence base for prescribing antidepressants for children and adolescents is smaller compared to the adult literature, properly understanding and prescribing these agents, and explaining their risks and benefits to families, can make a major difference in patient compliance, satisfaction, and outcomes. Antidepressants (particularly selective serotonin reuptake inhibitors) are the firstline pharmacologic intervention for pediatric patients with anxiety disorders, obsessive-compulsive disorder, or major depressive disorder.

Related Resource

• Bonin L, Moreland CS. Overview of prevention and treatment for pediatric depression. https://www.uptodate.com/contents/overview-of-prevention-and-treatment-for-pediatric-depression. Last reviewed July 2019.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Cimetidine • Tagamet
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fluvoxamine • Luvox
Imipramine • Tofranil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor
Vilazodone • Viibryd
Vortioxetine • Trintellix

Box 1

Box 2

Major depressive disorder (MDD) is a significant pediatric health problem, with a lifetime prevalence as high as 20% by the end of adolescence.^1-3 Major depressive disorder in adolescence is associated with significant morbidity, including poor social functioning, school difficulties, early pregnancy, and increased risk of physical illness and substance abuse.^4-6 It is also linked with significant mortality, with increased risk for suicide, which is now the second leading cause of death in individuals age 10 to 24 years.^1,7,8

As their name suggests, antidepressants comprise a group of medications that are used to treat MDD; they are also, however, first-line agents for generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD) in adults. Anxiety disorders (including GAD and other anxiety diagnoses) and PTSD are also common in childhood and adolescence with a combined lifetime prevalence ranging from 15% to 30%.^9,10 These disorders are also associated with increased risk of suicide.¹¹ For all of these disorders, depending on the severity of presentation and the preference of the patient, treatments are often a combination of psychotherapy and psychopharmacology.

Clinicians face several challenges when considering antidepressants for pediatric patients. Pediatricians and psychiatrists need to understand whether these medications work in children and adolescents, and whether there are unique developmental safety and tolerability issues. The evidence base in child psychiatry is considerably smaller compared with that of adult psychiatry. From this more limited evidence base also came the controversial “black-box” warning regarding a risk of emergent suicidality when starting antidepressants that accompanies all antidepressants for pediatric, but not adult, patients. This warning has had major effects on clinical encounters with children experiencing depression, including altering clinician prescribing behavior.¹²

In this article, we review the current evidence for antidepressant efficacy, tolerability, and safety in pediatric patients. We also suggest ways in which clinicians might choose, start, and stop antidepressants in children, as well as how to talk with parents about benefits, risks, and the black-box warning.

Do antidepressants work in children?

Selective serotonin reuptake inhibitors. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used class of antidepressants in both children and adults.¹³ While only a few SSRIs are FDA-approved for pediatric indications, the lack of FDA approval is typically related to a lack of sufficient testing in randomized controlled trials (RCTs) for specific pediatric indications, rather than to demonstrable differences in efficacy between antidepressant agents. Since there is currently no data to suggest inferiority of one agent compared to another in children or adults,^14,15 efficacy data will be discussed here as applied to the class of SSRIs, generalizing from RCTs conducted on individual drugs. Table 1 lists FDA indications and dosing information for individual antidepressants.

There is strong evidence that SSRIs are effective for treating pediatric anxiety disorders (eg, social anxiety disorder and GAD)¹⁶ and OCD,¹⁷ with numbers needed to treat (NNT) between 3 and 5. For both of these disorders, SSRIs combined with cognitive-behavioral therapy (CBT) have the highest likelihood of improving symptoms or achieving remission.^17,18

Selective serotonin reuptake inhibitors are also effective for treating pediatric MDD; however, the literature is more complex for this disorder compared to GAD and OCD as there are considerable differences in effect sizes between National Institute of Mental Health (NIMH)–funded studies and industry-sponsored trials.¹³ The major NIMH-sponsored adolescent depression trial, TADS (Treatment for Adolescents and Depression Study), showed that SSRIs (fluoxetine in this case) were quite effective, with an NNT of 4 over the acute phase (12 weeks).¹⁹ Ultimately, approximately 80% of adolescents improved over 9 months. Many industry-sponsored trials for MDD in pediatric patients had large placebo response rates (approximately 60%), which resulted in smaller between-group differences, and estimates of an NNT closer to 12,¹³ which has muddied the waters in meta-analyses that include all trials.²⁰ Improvement in depressive symptoms also appears to be bolstered by concomitant CBT in MDD,¹⁹ but not as robustly as in GAD and OCD. While the full benefit of SSRIs for depression may take as long as 8 weeks, a meta-analysis of depression studies of pediatric patients suggests that significant benefits from placebo are observed as early as 2 weeks, and that further treatment gains are minimal after 4 weeks.¹⁵ Thus, we recommend at least a 4- to 6-week trial at therapeutic dosing before deeming a medication a treatment failure.

Continue to: Posttraumatic stress disorder...

Posttraumatic stress disorder is a fourth disorder in which SSRIs are a first-line treatment in adults. The data for using SSRIs to treat pediatric patients with PTSD is scant, with only a few RCTs, and no large NIMH-funded trials. Randomized controlled trials have not demonstrated significant differences between SSRIs and placebo^21,22 and thus the current first-line recommendation in pediatric PTSD remains trauma-focused therapy, with good evidence for trauma-focused CBT.²³ Practically speaking, there can be considerable overlap of PTSD, depression, and anxiety symptoms in children,²³ and children with a history of trauma who also have comorbid MDD may benefit from medication if their symptoms persist despite an adequate trial of psychotherapy.

Taken together, the current evidence suggests that SSRIs are often effective in pediatric GAD, OCD, and MDD, with low NNTs (ranging from 3 to 5 based on NIMH-funded trials) for all of these disorders; there is not yet sufficient evidence of efficacy in pediatric patients with PTSD.

Fluoxetine has been studied more intensively than other SSRIs (for example, it was the antidepressant used in the TADS trial), and thus has the largest evidence base. For this reason, fluoxetine is often considered the first of the first-line options. Additionally, fluoxetine has a longer half-life than other antidepressants, which may make it more effective in situations where patients are likely to miss doses, and results in a lower risk of withdrawal symptoms when stopped due to “self-tapering.”

SNRIs and atypical antidepressants. Other antidepressants commonly used in pediatric patients but with far less evidence of efficacy include serotonin-norepinephrine reuptake inhibitors (SNRIs) and the atypical antidepressants bupropion and mirtazapine. The SNRI duloxetine is FDA-approved for treating GAD in children age 7 to 17, but there are no other pediatric indications for duloxetine, or for the other SNRIs.

In general, adverse effect profiles are worse for SNRIs compared to SSRIs, further limiting their utility. While there are no pediatric studies demonstrating SNRI efficacy for neuropathic pain, good data exists in adults.²⁴ Thus, an SNRI could be a reasonable option if a pediatric patient has failed prior adequate SSRI trials and also has comorbid neuropathic pain.

Continue to: Neither bupropion nor mirtazapine...

Neither bupropion nor mirtazapine have undergone rigorous testing in pediatric patients, and therefore these agents should generally be considered only once other first-line treatments have failed. Bupropion has been evaluated for attention-deficit/hyperactivity disorder (ADHD)²⁵ and for adolescent smoking cessation.²⁶ However, the evidence is weak, and bupropion is not considered a first-line option for children and adolescents.

Tricyclic antidepressants. Randomized controlled trials have demonstrated that tricyclic antidepressants (TCAs) are efficacious for treating several pediatric conditions; however, their significant side effect profile, their monitoring requirements, as well as their lethality in overdose has left them replaced by SSRIs in most cases. That said, they can be appropriate in refractory ADHD (desipramine^27,28) and refractory OCD (clomipramine is FDA-approved for this indication²⁹); they are considered a third-line treatment for enuresis.³⁰

Why did my patient stop the medication?

Common adverse effects. Although the greatest benefit of antidepressant medications compared with placebo is achieved relatively early on in treatment, it generally takes time for these benefits to accrue and become clinically apparent.^15,31 By contrast, most adverse effects of antidepressants present and are at their most severe early in treatment. The combination of early adverse effects and delayed efficacy leads many patients, families, and clinicians to discontinue medications before they have an adequate chance to work. Thus, it is imperative to provide psychoeducation before starting a medication about the typical time-course of improvement and adverse effects (Table 2).

Adverse effects of SSRIs often appear or worsen transiently during initiation of a medication, during a dose increase,³² or, theoretically, with the addition of a medication that interferes with SSRI metabolism (eg, cimetidine inhibition of cytochrome P450 2D6).³³ If families are prepared for this phenomenon and the therapeutic alliance is adequate, adverse effects can be tolerated to allow for a full medication trial. Common adverse effects of SSRIs include sleep problems (insomnia/sedation), gastrointestinal upset, sexual dysfunction, dry mouth, and hyperhidrosis. Although SSRIs differ somewhat in the frequency of these effects, as a class, they are more similar than different. Adequate psychoeducation is especially imperative in the treatment of OCD and anxiety disorders, where there is limited evidence of efficacy for any non-serotonergic antidepressants.

Serotonin-norepinephrine reuptake inhibitors are not considered first-line medications because of the reduced evidence base compared to SSRIs and their enhanced adverse effect profiles. Because SNRIs partially share a mechanism of action with SSRIs, they also share portions of the adverse effects profile. However, SNRIs have the additional adverse effect of hypertension, which is related to their noradrenergic activity. Thus, it is reasonable to obtain a baseline blood pressure before initiating an SNRI, as well as periodically after initiation and during dose increases, particularly if the patient has other risk factors for hypertension.³⁴

Continue to: Although TCAs have efficacy...

Although TCAs have efficacy in some pediatric disorders,^27-29,35 their adverse effect profile limits their use. Tricyclic antidepressants are highly anticholinergic (causing dizziness secondary to orthostatic hypotension, dry mouth, and urinary retention) and antihistaminergic (causing sedation and weight gain). Additionally, TCAs lower the seizure threshold and have adverse cardiac effects relating to their anti-alpha-1 adrenergic activity, resulting in dose-dependent increases in the QTc and cardiac toxicity in overdose that could lead to arrhythmia and death. These medications have their place, but their use requires careful informed consent, clear treatment goals, and baseline and periodic cardiac monitoring (via electrocardiogram).

Serious adverse effects. Clinicians may be hesitant to prescribe antidepressants for pediatric patients because of the potential for more serious adverse effects, including severe behavioral activation syndromes, serotonin syndrome, and emergent suicidality. However, current FDA-approved antidepressants arguably have one of the most positive risk/benefit profiles of any orally-administered medication approved for pediatric patients. Having a strong understanding of the evidence is critical to evaluating when it is appropriate to prescribe an antidepressant, how to properly monitor the patient, and how to obtain accurate informed consent.

Pediatric behavioral activation syndrome. Many clinicians report that children receiving antidepressants experience a pediatric behavioral activation syndrome, which exists along a spectrum from mild activation, increased energy, insomnia, or irritability up through more severe presentations of agitation, hyperactivity, or possibly mania. A recent meta-analysis suggested a positive association between antidepressant use and activation events on the milder end of this spectrum in pediatric patients with non-OCD anxiety disorders,¹⁶ and it is thought that compared with adolescents, younger children are more susceptible to activation adverse effects.³⁶ The likelihood of activation events has been associated with higher antidepressant plasma levels,³⁷ suggesting that dose or individual differences in metabolism may play a role. At the severe end of the spectrum, the risk of induction of mania in pediatric patients with depression or anxiety is relatively rare (<2%) and not statistically different from placebo in RCTs of pediatric participants.³⁸ Meta-analyses of larger randomized, placebo-controlled trials of adults do not support the idea that SSRIs and other second-generation antidepressants carry an increased risk of mania compared with placebo.^39,40 Children or adolescents with bona fide bipolar disorder (ie, patients who have had observed mania that meets all DSM-5 criteria) should be treated with a mood-stabilizing agent or antipsychotic if prescribed an antidepressant.⁴¹ These clear-cut cases are, however, relatively rare, and more often clinicians are confronted with ambiguous cases that include a family history of bipolar disorder along with “softer” symptoms of irritability, intrusiveness, or aggression. In these children, SSRIs may be appropriate for depressive, OCD, or anxiety symptoms, and should be strongly considered before prescribing antipsychotics or mood stabilizers, as long as initiated with proper monitoring.

Serotonin syndrome is a life-threatening condition caused by excess synaptic serotonin. It is characterized by confusion, sweating, diarrhea, hypertension, hyperthermia, and tachycardia. At its most severe, serotonin syndrome can result in seizures, arrhythmias, and death. The risk of serotonin syndrome is very low when using an SSRI as monotherapy. Risk increases with polypharmacy, particularly unexamined polypharmacy when multiple serotonergic agents are inadvertently on board. Commonly used serotonergic agents include other antidepressants, migraine medications (eg, triptans), some pain medications, and the cough suppressant dextromethorphan.

The easiest way to mitigate the risk of serotonin syndrome is to use an interaction index computer program, which can help ensure that the interacting agents are not prescribed without first discussing the risks and benefits. It is important to teach adolescents that certain recreational drugs are highly serotonergic and can cause serious interactions with antidepressants. For example, recreational use of dextrometh­orphan or 3,4-methylenedioxymethamphetamine (MDMA; commonly known as “ecstasy”) has been associated with serotonin syndrome in adolescents taking antidepressant medications.^42,43

Continue to: Suicidality

Suicidality. The black-box warning regarding a risk of emergent suicidality when starting antidepressant treatment in children is controversial.⁴⁴ The prospect that a medication intended to ameliorate depression might instead risk increasing suicidal thinking is alarming to parents and clinicians alike. To appropriately weigh and discuss the risks and benefits with families, it is important to understand the data upon which the warning is based.

In 2004, the FDA commissioned a review of 23 antidepressant trials, both published and unpublished, pooling studies across multiple indications (MDD, OCD, anxiety, and ADHD) and multiple antidepressant classes. This meta-analysis, which included nearly 4,400 pediatric patients, found a small but statistically significant increase in spontaneously-reported suicidal thoughts or actions, with a risk difference of 1% (95% confidence interval [CI], 1% to 2%).⁴⁵ These data suggest that if one treats 100 pediatric patients, 1 to 2 of them may experience short-term increases in suicidal thinking or behavior.⁴⁵ There were no differences in suicidal thinking when assessed systematically (ie, when all subjects reported symptoms of suicidal ideation on structured rating scales), and there were no completed suicides.⁴⁵ A subsequent analysis that included 27 pediatric trials suggested an even lower, although still significant, risk difference (<1%), yielding a number needed to harm (NNH) of 143.⁴⁶ Thus, with low NNT for efficacy (3 to 6) and relatively high NNH for emergent suicidal thoughts or behaviors (100 to 143), for many patients the benefits will outweigh the risks.

Figure 1, Figure 2, and Figure 3 are Cates plots that depict the absolute benefits of antidepressants compared with the risk of suicidality for pediatric patients with MDD, OCD, and anxiety disorders. Recent meta-analyses have suggested that the increased risk of suicidality in antidepressant trials is specific to studies that included children and adolescents, and is not observed in adult studies. A meta-analysis of 70 trials involving 18,526 participants suggested that the odds ratio of suicidality in trials of children and adolescents was 2.39 (95% CI, 1.31 to 4.33) compared with 0.81 (95% CI, 0.51 to 1.28) in adults.⁴⁷ Additionally, a network meta-analysis exclusively focusing on pediatric antidepressant trials in MDD reported significantly higher suicidality-related adverse events in venlafaxine trials compared with placebo, duloxetine, and several SSRIs (fluoxetine, paroxetine, and escitalopram).²⁰ These data should be interpreted with caution as differences in suicidality detected between agents is quite possibly related to differences in the method of assessment between trials, as opposed to actual differences in risk between agents.

Epidemiologic data further support the use of antidepressants in pediatric patients, showing that antidepressant use is associated with decreased teen suicide attempts and completions,⁴⁸ and the decline in prescriptions that occurred following the black-box warning was accompanied by a 14% increase in teen suicides.⁴⁹ Multiple hypotheses have been proposed to explain the pediatric clinical trial findings. One idea is that potential adverse effects of activation, or the intended effects of restoring the motivation, energy, and social engagement that is often impaired in depression, increases the likelihood of thinking about suicide or acting on thoughts. Another theory is that reporting of suicidality may be increased, rather than increased de novo suicidality itself. Antidepressants are effective for treating pediatric anxiety disorders, including social anxiety disorder,¹⁶ which could result in more willingness to report. Also, the manner in which adverse effects are generally ascertained in trials might have led to increased spontaneous reporting. In many trials, investigators ask whether participants have any adverse effects in general, and inquire about specific adverse effects only if the family answers affirmatively. Thus, the increased rate of other adverse effects associated with antidepressants (sleep problems, gastrointestinal upset, dry mouth, etc.) might trigger a specific question regarding suicidal ideation, which the child or family then may be more likely to report. Alternatively, any type of psychiatric treatment could increase an individual’s propensity to report; in adolescent psychotherapy trials, non-medicated participants have reported emergent suicidality at similar frequencies as those described in drug trials.⁵⁰ Regardless of the mechanism, the possibility of treatment-emergent suicidality is a low-frequency but serious event that necessitates careful monitoring when starting medication. Current guidelines suggest seeing children weekly for the first month after medication initiation, every 2 weeks for the following month, and monthly thereafter.⁵¹

Continue to: How long should the antidepressant be continued?

How long should the antidepressant be continued?

Many patients are concerned about how long they may be taking medication, and whether they will be taking an antidepressant “forever.” A treatment course can be broken into an acute phase, wherein remission is achieved and maintained for 6 to 8 weeks. This is followed by a continuation phase, with the goal of relapse prevention, lasting 16 to 20 weeks. The length of the last phase—the maintenance phase—depends both on the child’s history, the underlying therapeutic indication, the adverse effect burden experienced, and the family’s preferences/values. In general, for a first depressive episode, after treating for 1 year, a trial of discontinuation can be attempted with close monitoring. For a second depressive episode, we recommend 2 years of remission on antidepressant therapy before attempting discontinuation. In patients who have had 3 depressive episodes, or have had episodes of high severity, we recommend continuing antidepressant treatment indefinitely. Although much less well studied, the risk of relapse following SSRI discontinuation appears much more significant in OCD, whereas anxiety disorders and MDD have a relatively comparable risk.⁵²

In general, stopping an antidepressant should be done carefully and slowly. The speed with which a specific antidepressant can be stopped is largely related to its half-life. Agents with very long half-lives, such as fluoxetine (half-life of 5 days for the parent compound and 9 days for active metabolite), can often be stopped altogether, being “auto-tapered” by the long half-life. One might still consider a taper if the patient were taking high doses. Medications with shorter half-lives must be more carefully tapered to avoid discontinuation syndromes. Discontinuation syndromes are characterized by flu-like symptoms (nausea, myalgias, fatigue, dizziness) and worsening mood. Medications with short half-lives (eg, paroxetine and venlafaxine) have the highest potential for this syndrome in children,⁵³ and thus are used less frequently.

What to do when first-line treatments fail

When a child does not experience sufficient improvement from first-line treatments, it is crucial to determine whether they have experienced an adequate dosing, duration, and quality of medication and psychotherapy.

Adequate psychotherapy? To determine whether children are receiving adequate CBT, ask:

1. if the child receives homework from psychotherapy
2. if the parents are included in treatment
3. if therapy has involved identifying thought patterns that may be contributing to the child’s illness, and
4. if the therapist has ever exposed the child to a challenge likely to produce anxiety or distress in a supervised environment and has developed an exposure hierarchy (for conditions with primarily exposure-based therapies, such as OCD or anxiety disorders).

If a family is not receiving most of these elements in psychotherapy, this is a good indicator that they may not be receiving evidence-based CBT.

Continue to: Adequate pharmacotherapy?

Adequate pharmacotherapy? Similarly, when determining the adequacy of previous pharmacotherapy, it is critical to determine whether the child received an adequate dose of medications (at least the FDA-recommended minimum dose) for an adequate duration of time at therapeutic dosing (at least 6 weeks for MDD, 8 weeks for anxiety disorders, and 8 to 12 weeks for pediatric patients with OCD), and that the child actually took the medication regularly during that period. Patient compliance can typically be tracked through checking refill requests or intervals through the patient’s pharmacy. Ensuring proper delivery of first-line treatments is imperative because (1) the adverse effects associated with second-line treatments are often more substantial; (2) the cost in terms of time and money is considerably higher with second-line treatments, and; (3) the evidence regarding the benefits of these treatments is much less certain.

Inadequate dosing is a common reason for non-response in pediatric patients. Therapeutic dose ranges for common antidepressants are displayed in Table 1. Many clinicians underdose antidepressants for pediatric patients initially (and often throughout treatment) because they fear that the typical dose titration used in clinical trials will increase the risk of adverse effects compared with more conservative dosing. There is limited evidence to suggest that this underdosing strategy is likely to be successful; adverse effects attributable to these medications are modest, and most that are experienced early in treatment (eg, headache, increased anxiety or irritability, sleep problems, gastrointestinal upset) are self-limiting and may be coincidental rather than medication-induced. Furthermore, there is no evidence for efficacy of subtherapeutic dosing in children in the acute phase of treatment or for preventing relapse.¹⁴ Thus, from an efficacy standpoint, a medication trial has not officially begun until the therapeutic dose range is reached.

Once dosing is within the therapeutic range, however, pediatric data differs from the adult literature. In most adult psychi­atric conditions, higher doses of SSRIs within the therapeutic range are associated with an increased response rate.^14,54 In pediatrics, there are few fixed dose trials, and once within the recommended therapeutic range, minimal data supports an association between higher dosing and higher efficacy.¹⁴ In general, pediatric guidelines are silent regarding optimal dosing of SSRIs within the recommended dose range, and higher antidepressant doses often result in a more significant adverse effect burden for children. One exception is pediatric OCD, where, similar to adults, the guidelines suggest that higher dosing of SSRIs often is required to induce a therapeutic response as compared to MDD and GAD.^31,55

If a child does not respond to adequate first-line treatment (or has a treatment history that cannot be fully verified), repeating these first-line interventions carries little risk and can be quite effective. For example, 60% of adolescents with MDD who did not initially respond to an SSRI demonstrated a significant response when prescribed a second SSRI or venlafaxine (with or without CBT).⁵⁶

When pediatric patients continue to experience significantly distressing and/or debilitating symptoms (particularly in MDD) despite multiple trials of antidepressants and psychotherapy, practitioners should consider a careful referral to interventional psychiatry services, which can include the more intensive treatments of electroconvulsive therapy, repetitive transcranial magnetic stimulation, or ketamine (see Box 1). Given the substantial morbidity and mortality associated with adolescent depression, interventional psychiatry treatments are under-researched and under-utilized clinically in pediatric populations.

Continue to: Antidepressants in general...

Antidepressants in general, and SSRIs in particular, are the first-line pharmacotherapy for pediatric anxiety, OCD, and MDD. For PTSD, although they are a first-line treatment in adults, their efficacy has not been demonstrated in children and adolescents. Antidepressants are generally safe, well-tolerated, and effective, with low NNTs (3 to 5 for anxiety and OCD; 4 to 12 in MDD, depending on whether industry trials are included). It is important that clinicians and families be educated about possible adverse effects and their time course in order to anticipate difficulties, ensure adequate informed consent, and monitor appropriately. The black-box warning regarding treatment-emergent suicidal thoughts or behaviors must be discussed (for suggested talking points, see Box 2). The NNH is large (100 to 143), and for many patients, the benefits will outweigh the risks. For pediatric patients who fail to respond to multiple adequate trials of antidepressants and psychotherapy, referrals for interventional psychiatry consultation should be considered.

Bottom Line

Although the evidence base for prescribing antidepressants for children and adolescents is smaller compared to the adult literature, properly understanding and prescribing these agents, and explaining their risks and benefits to families, can make a major difference in patient compliance, satisfaction, and outcomes. Antidepressants (particularly selective serotonin reuptake inhibitors) are the firstline pharmacologic intervention for pediatric patients with anxiety disorders, obsessive-compulsive disorder, or major depressive disorder.

Related Resource

• Bonin L, Moreland CS. Overview of prevention and treatment for pediatric depression. https://www.uptodate.com/contents/overview-of-prevention-and-treatment-for-pediatric-depression. Last reviewed July 2019.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Cimetidine • Tagamet
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fluvoxamine • Luvox
Imipramine • Tofranil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor
Vilazodone • Viibryd
Vortioxetine • Trintellix

Box 1

Box 2

Psoriasis is a chronic cutaneous disease associated with immune-mediated inflammation. The disease has a complex etiology, with factors such as genetics, smoking, alcohol use, diet, and stress all believed to be implicated in its appearance and severity. Specific factors, including increased body mass index and weight gain, have been associated with a higher prevalence of psoriasis and are risk factors for the disease. Because psoriasis varies in severity and incidence, patients often can experience a substantial negative impact on their quality of life, with increased incidences of anxiety and depression.¹ Because diet is an accessible and controllable variable, many patients choose to alter their diets to help relieve symptoms of the disease. This article aims to review and summarize the existing literature for possible relationships and correlations between diet and psoriasis.

Because diet is a factor contributing to psoriasis, it is a lifestyle change that patients often make. In a 2017 survey of 1206 patients with psoriasis, 86% reported modifying their diets.² Furthermore, when patients were compared with control individuals of the same sex and of similar age, it was shown that those with psoriasis consumed statistically significant lower amounts of sugar, whole-grain fiber, dairy products, and calcium (P<.001). The survey also found that patient diets included significantly more fruits, vegetables, and legumes (P<.01). Although no single diet was adhered to by patients, 40% did report attempting a specialized diet to improve their psoriasis. The most common diets were gluten free (35.6%), low carbohydrate/high protein (16.6%), and Paleolithic (11.6%). In addition to these diets, the Mediterranean diet and a vegetarian diet were both among those reported to improve psoriatic symptoms. Finally, certain foods stood out as more frequently reported to affect symptoms, particularly fish oil, fruits, vegetables, and water, which were all reported by at least 10% of respondents to positively affect their psoriasis. Reductions in consumption of alcohol, gluten, nightshades, and junk foods were associated with skin improvements in at least 50% of patients.² These baseline differences in diet informed our search of the literature and showed that dietary changes can serve as an important adjunct to treatment for many patients.

Mediterranean Diet

The Mediterranean diet consists of a high amount of fruits, vegetables, nuts and legumes, cereals, and olive oil, while restricting consumption of red meats, dairy products, and alcohol (besides red wine) at meals.³ Adherence to the diet has been associated with a reduced risk for cardiovascular diseases,⁴ rheumatoid arthritis, and Crohn disease,³ among others, possibly because the diet contains a high proportion and variety of foods that contain antioxidants and anti-inflammatory compounds, including the monounsaturated fatty acids (MUFAs) in olive oil and the polyphenols in fruits and vegetables. Consumption of both MUFAs and highly anti-inflammatory nutrients has been associated with reduced prevalence of risk factors for chronic inflammatory diseases, and consumption levels of MUFAs in particular have been reported to be a predictive factor in psoriasis severity.³

Recent studies have tried to quantify an association between consumption of the Mediterranean diet and psoriasis. One cross-sectional study in 2015 evaluated 62 patients with psoriasis for their adherence to the Mediterranean diet and psoriasis severity.⁴ Utilizing a 14-question evaluation, the study found that patients with a higher severity of psoriasis, as evaluated by a psoriasis area and severity index (PASI) score and C-reactive protein levels, had a lower adherence to the diet. Notably, consumption of extra-virgin olive oil was found to be an independent predictor of PASI score, and consumption of fish was an independent predictor of C-reactive protein levels.⁴

A second cross-sectional questionnaire study found similar results in a larger population of 3557 patients. The same association between patients with severe psoriasis and low levels of adherence to the Mediterranean diet was reported.³ Although neither study showed a causal relationship between the diet and psoriasis severity, both did report the potential impacts of proinflammatory and anti-inflammatory foods. General foods and nutrients listed by the studies as having anti-inflammatory properties include MUFAs; fish; vitamins A, C, D, and E; and omega-3 fatty acids.³ Because of the large number of confounding factors in dietary studies that rely on questionnaires, it is hard to definitively label the Mediterranean diet as beneficial topsoriasis. However, individual components of the diet may be used as predictors of psoriasis severity, and the diet itself may be used in tandem with other treatments for psoriasis.

Gluten-Free Diet

Celiac disease is an inflammatory enteropathy caused by an immune reaction to the protein gliadin, which is found in foods containing gluten, such as wheat.⁵ Immune system assault on the intestinal enterocytes leads to the stripping away of villi, negatively affecting nutrient absorption. Multiple studies have reported an association between having psoriasis and having celiac disease as well as the reverse, including a 3-fold increased risk of celiac disease for patients with psoriasis in a 2017 meta-analysis.⁶ Even if patients with psoriasis did not have celiac disease, studies have found that a notable percentage of patients with psoriasis have elevated antigliadin IgA antibody levels.⁷ Many hypotheses have been proposed to explain this association. One article suggested that the malabsorption associated with celiac disease predisposes patients to vitamin D deficiency, which is a contributing risk factor for psoriasis.⁸ Other explanations involve common immune cells involved in the response to both diseases and a shared genetic background between the 2 diseases.⁸ As a gluten-free diet is standard for patients with celiac disease, it stands to reason that IgA could be used as a serum biomarker for patients who also could see improvements by adopting the diet.

This result could help explain the proportion of respondents to the 2017 survey who experienced improvements to their psoriasis if the gluten-free diet was in fact not triggering the inflammatory effects that a regular diet would, which also may help to explain the mixed results that the gluten-free diet has had as a treatment for psoriasis. One 3-month study of patients who were positive for antigliadin antibodies found that the majority (82%) experienced a decrease in antibody levels and affected skin area after following a gluten-free diet. Only half the patients had been diagnosed with celiac disease prior to the study, lending credibility to the idea that antigliadin antibody could be used as a marker for patients with psoriasis who would benefit from a gluten-free diet.⁹ Other case studies have reported no improvement of psoriasis following implementation of a gluten-free diet,¹⁰ despite the patients having elevated gliadin antibodies or celiac disease. More studies are required to discern the exact nature of the benefits of a gluten-free diet on psoriasis; however, it does serve as a promising option for patients with both psoriasis and celiac disease.

Ketogenic Diet

As obesity and weight gain are factors associated with psoriasis, some patients turn to diets that restrict calories with the goal of losing weight to improve their symptoms. One 2015 case report studied a patient who restored her response to systemic treatment of psoriasis following an intensive 4-week, calorie-restricted ketogenic diet.¹¹ The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet. Animal studies have shown the diet to have anti-inflammatory effects, including lowering levels of proinflammatory cytokines and reduced fever.¹² In the 2015 case report, the rapid and consistent weight loss experienced by the patient because of the ketogenic diet was thought to be the cause of the restoration of treatment effectiveness,¹¹ which is interesting, since the role of the ketogenic diet was not to supplement any deficiencies but to move the patient to a physiologic state that was once again receptive to treatment. This finding suggests that a variety of diets could improve psoriasis symptoms, so long as they do not cause inflammation or reduce overall body mass. One study of patients on a calorie-restricted diet over 8 weeks did see a trend of patients on the diet showing improvement in both their PASI scores and Dermatology Life Quality Index, though the improvement was not statistically significant.¹³ To determine if the ketogenic diet has a significant association with psoriasis improvement, controlled, large-population studies should be performed in the future with age, sex, and weight-matched controls, which may be difficult to do. Further studies looking at the association between weight loss and psoriasis also could be another direction.

Vegetarian Diet

Both vegetarian and vegan diets have been evaluated for their efficacy in relieving symptoms of chronic inflammatory disorders. Although the 2 diets are similar in avoiding consumption of meat, fish, and poultry, vegan diets often have additional food restrictions, including avoiding eggs, honey, and dairy products. One study noted the impact of these diets on patients with a variety of skin conditions following a period of fasting. It was observed that some patients with psoriasis saw an improvement in their symptoms during the period when they were eating a vegetarian or vegan diet, which was attributed to a return to normal levels of activity of neutrophils, extrapolated from serum levels of lactoferrin.¹⁴ Vegetarian diets have been shown to be associated with higher ratios of anti-inflammatory to proinflammatory adipokines compared to omnivorous diets,¹⁵ as well as lower expression levels of proinflammatory genes in the gut microbiota and lower expression levels of IgE.¹⁶ Perhaps the anti-inflammatory impacts of the diet affected the symptoms of psoriasis. The benefits of a vegetarian diet also have been attributed to the high amount of potassium consumed,¹⁷ which is used in the body to synthesize cortisol, a common treatment for psoriasis. Potassium supplementation has been shown to raise serum cortisol levels in patients.⁶ Although additional studies are needed to discern the significance of potassium in the vegetarian diet, both hypotheses are reasonable explanations for the observations seen in these studies.

Vitamin D and Other Nutritional Supplements

Because it is not always feasible for patients to alter their diets, many have turned to dietary supplements as an alternative method of treatment and lifestyle change. Two of the more prominently represented nutritional additives in the literature are fish oils and vitamin D.¹⁸ Supplemental vitamin D is a prohormone that can be endogenously converted to its active 1,25-dihydroxyvitamin D.¹⁹ Vitamin D plays important roles in the regulation of calcium and magnesium in the bones as well as the maturation and differentiation of keratinocytes in the skin.¹⁶ Topical vitamin D analogues are standard treatments for psoriasis, as they are used to modulate the immune system to great effect.²⁰ Some patients with psoriasis present with vitamin D insufficiency,²¹ and it stands to reason that oral supplementation may be a treatment option. There have been multiple studies assessing the efficacy of oral vitamin D for the treatment of psoriasis; however, in the only randomized and placebo-controlled trial, there was only a slight nonsignificant improvement in the group supplemented with vitamin D.²⁰ Another small, open-label study reported remarkably improved PASI scores in 9 vitamin D–supplemented, dietary calcium–restricted patients.²² The lack of recent, large-sample studies makes it hard to draw notable conclusions from these studies.

The polyunsaturated fatty acids found in fish oils also have been considered as a treatment option for psoriasis.²³ Millsop et al²⁰ conducted an analysis of the literature reviewing the efficacy of fish oil in the treatment of psoriasis. Twelve of 15 compiled trials showed an improvement in psoriasis, ranging from slight improvements from baseline levels of the disease to statistically significant decreases in PASI scores (P<.05). It is notable that the amount of fish oil given in these studies varied widely, but the amount given did not necessarily correlate with strength of impact.²⁰ For example, Mayser et al,²⁴ Bittiner et al,²⁵ and Grimminger et al²⁶ each performed prospective, double-blind studies with docosahexaenoic acid and eicosapentaenoic acid (the omega-3 fatty acids found in fish oils), and all 3 studies saw improvements in the omega-3–treated group vs the control group. The doses of the oils, however, ranged from as low as 1.2 and 1.8 g daily of docosahexaenoic acid and eicosapentaenoic acid, respectively, to 4.2 g daily of each fatty acid.^24-26

Studies also have shown little to no improvement in the use of fish oil to treat psoriasis. One such study was conducted by Soyland et al²⁷ in 1993 in Norway. Utilizing a prospective, double-blind, placebo-controlled design over 4 months on 145 patients with moderate to severe psoriasis, researchers evaluated the treatment effectiveness via PASI scores; subjective reports from the patients; clinical manifestations; and factors such as cellular infiltration, desquamation, and redness. The results were mixed, with the placebo (corn oil) group having less redness and cellular desquamation and the fish oil group showing less cellular infiltration. In the other categories, there was no significant difference between the 2 groups, and researchers concluded there was no significant benefit to treating psoriasis using fish oil vs corn oil.²⁷ As with many of the other diets, there have been no recent, large-scale studies performed on the effect of fish oil supplementation on psoriasis; however, of the studies we reviewed, none showed fish oil supplementation to have a significant negative impact on psoriasis.

Conclusion

Dietary modifications have a complex multifactorial effect on psoriasis, often dependent on the variations of psoriasis and the lifestyle of the patient, including level of exercise, activities such as smoking and drinking, and genetic susceptibilities to conditions such as obesity. Thus, it is difficult for one diet to have a significant impact on psoriasis symptoms that applies to the majority of individuals. However, it appears that certain foods or nutritional supplements can be modified from all diets for general improvement. Foods with systemic anti-inflammatory effects, such as olive oil and fish oil, seem to be beneficial in treating psoriasis. As an extension, a gluten-free diet may help psoriasis patients with celiac disease by reducing the inflammatory environment of the body. On the opposite side of the spectrum, proinflammatory foods such as dietary fat and alcohol should be avoided.²⁸

In general, larger and more recent population-based studies are needed to add to the literature on this subject. Nationwide voluntary web-based surveys such as the NutriNet-Santé study in France may be one way to quickly amass large quantities of data (ClinicalTrials.gov Identifier NCT03335644). Participants are recruited through multimedia campaigns and return online questionnaires annually for 1 decade. A subset of participants also contributes biologic samples and participates in clinical examinations. This type of data gathering would capture many variables, provide a large sample size, and perhaps shed light on regional differences in diet and lifestyle that could then be targeted with treatments.

Psoriasis is a chronic cutaneous disease associated with immune-mediated inflammation. The disease has a complex etiology, with factors such as genetics, smoking, alcohol use, diet, and stress all believed to be implicated in its appearance and severity. Specific factors, including increased body mass index and weight gain, have been associated with a higher prevalence of psoriasis and are risk factors for the disease. Because psoriasis varies in severity and incidence, patients often can experience a substantial negative impact on their quality of life, with increased incidences of anxiety and depression.¹ Because diet is an accessible and controllable variable, many patients choose to alter their diets to help relieve symptoms of the disease. This article aims to review and summarize the existing literature for possible relationships and correlations between diet and psoriasis.

Because diet is a factor contributing to psoriasis, it is a lifestyle change that patients often make. In a 2017 survey of 1206 patients with psoriasis, 86% reported modifying their diets.² Furthermore, when patients were compared with control individuals of the same sex and of similar age, it was shown that those with psoriasis consumed statistically significant lower amounts of sugar, whole-grain fiber, dairy products, and calcium (P<.001). The survey also found that patient diets included significantly more fruits, vegetables, and legumes (P<.01). Although no single diet was adhered to by patients, 40% did report attempting a specialized diet to improve their psoriasis. The most common diets were gluten free (35.6%), low carbohydrate/high protein (16.6%), and Paleolithic (11.6%). In addition to these diets, the Mediterranean diet and a vegetarian diet were both among those reported to improve psoriatic symptoms. Finally, certain foods stood out as more frequently reported to affect symptoms, particularly fish oil, fruits, vegetables, and water, which were all reported by at least 10% of respondents to positively affect their psoriasis. Reductions in consumption of alcohol, gluten, nightshades, and junk foods were associated with skin improvements in at least 50% of patients.² These baseline differences in diet informed our search of the literature and showed that dietary changes can serve as an important adjunct to treatment for many patients.

Mediterranean Diet

The Mediterranean diet consists of a high amount of fruits, vegetables, nuts and legumes, cereals, and olive oil, while restricting consumption of red meats, dairy products, and alcohol (besides red wine) at meals.³ Adherence to the diet has been associated with a reduced risk for cardiovascular diseases,⁴ rheumatoid arthritis, and Crohn disease,³ among others, possibly because the diet contains a high proportion and variety of foods that contain antioxidants and anti-inflammatory compounds, including the monounsaturated fatty acids (MUFAs) in olive oil and the polyphenols in fruits and vegetables. Consumption of both MUFAs and highly anti-inflammatory nutrients has been associated with reduced prevalence of risk factors for chronic inflammatory diseases, and consumption levels of MUFAs in particular have been reported to be a predictive factor in psoriasis severity.³

Recent studies have tried to quantify an association between consumption of the Mediterranean diet and psoriasis. One cross-sectional study in 2015 evaluated 62 patients with psoriasis for their adherence to the Mediterranean diet and psoriasis severity.⁴ Utilizing a 14-question evaluation, the study found that patients with a higher severity of psoriasis, as evaluated by a psoriasis area and severity index (PASI) score and C-reactive protein levels, had a lower adherence to the diet. Notably, consumption of extra-virgin olive oil was found to be an independent predictor of PASI score, and consumption of fish was an independent predictor of C-reactive protein levels.⁴

A second cross-sectional questionnaire study found similar results in a larger population of 3557 patients. The same association between patients with severe psoriasis and low levels of adherence to the Mediterranean diet was reported.³ Although neither study showed a causal relationship between the diet and psoriasis severity, both did report the potential impacts of proinflammatory and anti-inflammatory foods. General foods and nutrients listed by the studies as having anti-inflammatory properties include MUFAs; fish; vitamins A, C, D, and E; and omega-3 fatty acids.³ Because of the large number of confounding factors in dietary studies that rely on questionnaires, it is hard to definitively label the Mediterranean diet as beneficial topsoriasis. However, individual components of the diet may be used as predictors of psoriasis severity, and the diet itself may be used in tandem with other treatments for psoriasis.

Gluten-Free Diet

Celiac disease is an inflammatory enteropathy caused by an immune reaction to the protein gliadin, which is found in foods containing gluten, such as wheat.⁵ Immune system assault on the intestinal enterocytes leads to the stripping away of villi, negatively affecting nutrient absorption. Multiple studies have reported an association between having psoriasis and having celiac disease as well as the reverse, including a 3-fold increased risk of celiac disease for patients with psoriasis in a 2017 meta-analysis.⁶ Even if patients with psoriasis did not have celiac disease, studies have found that a notable percentage of patients with psoriasis have elevated antigliadin IgA antibody levels.⁷ Many hypotheses have been proposed to explain this association. One article suggested that the malabsorption associated with celiac disease predisposes patients to vitamin D deficiency, which is a contributing risk factor for psoriasis.⁸ Other explanations involve common immune cells involved in the response to both diseases and a shared genetic background between the 2 diseases.⁸ As a gluten-free diet is standard for patients with celiac disease, it stands to reason that IgA could be used as a serum biomarker for patients who also could see improvements by adopting the diet.

This result could help explain the proportion of respondents to the 2017 survey who experienced improvements to their psoriasis if the gluten-free diet was in fact not triggering the inflammatory effects that a regular diet would, which also may help to explain the mixed results that the gluten-free diet has had as a treatment for psoriasis. One 3-month study of patients who were positive for antigliadin antibodies found that the majority (82%) experienced a decrease in antibody levels and affected skin area after following a gluten-free diet. Only half the patients had been diagnosed with celiac disease prior to the study, lending credibility to the idea that antigliadin antibody could be used as a marker for patients with psoriasis who would benefit from a gluten-free diet.⁹ Other case studies have reported no improvement of psoriasis following implementation of a gluten-free diet,¹⁰ despite the patients having elevated gliadin antibodies or celiac disease. More studies are required to discern the exact nature of the benefits of a gluten-free diet on psoriasis; however, it does serve as a promising option for patients with both psoriasis and celiac disease.

Ketogenic Diet

As obesity and weight gain are factors associated with psoriasis, some patients turn to diets that restrict calories with the goal of losing weight to improve their symptoms. One 2015 case report studied a patient who restored her response to systemic treatment of psoriasis following an intensive 4-week, calorie-restricted ketogenic diet.¹¹ The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet. Animal studies have shown the diet to have anti-inflammatory effects, including lowering levels of proinflammatory cytokines and reduced fever.¹² In the 2015 case report, the rapid and consistent weight loss experienced by the patient because of the ketogenic diet was thought to be the cause of the restoration of treatment effectiveness,¹¹ which is interesting, since the role of the ketogenic diet was not to supplement any deficiencies but to move the patient to a physiologic state that was once again receptive to treatment. This finding suggests that a variety of diets could improve psoriasis symptoms, so long as they do not cause inflammation or reduce overall body mass. One study of patients on a calorie-restricted diet over 8 weeks did see a trend of patients on the diet showing improvement in both their PASI scores and Dermatology Life Quality Index, though the improvement was not statistically significant.¹³ To determine if the ketogenic diet has a significant association with psoriasis improvement, controlled, large-population studies should be performed in the future with age, sex, and weight-matched controls, which may be difficult to do. Further studies looking at the association between weight loss and psoriasis also could be another direction.

Vegetarian Diet

Both vegetarian and vegan diets have been evaluated for their efficacy in relieving symptoms of chronic inflammatory disorders. Although the 2 diets are similar in avoiding consumption of meat, fish, and poultry, vegan diets often have additional food restrictions, including avoiding eggs, honey, and dairy products. One study noted the impact of these diets on patients with a variety of skin conditions following a period of fasting. It was observed that some patients with psoriasis saw an improvement in their symptoms during the period when they were eating a vegetarian or vegan diet, which was attributed to a return to normal levels of activity of neutrophils, extrapolated from serum levels of lactoferrin.¹⁴ Vegetarian diets have been shown to be associated with higher ratios of anti-inflammatory to proinflammatory adipokines compared to omnivorous diets,¹⁵ as well as lower expression levels of proinflammatory genes in the gut microbiota and lower expression levels of IgE.¹⁶ Perhaps the anti-inflammatory impacts of the diet affected the symptoms of psoriasis. The benefits of a vegetarian diet also have been attributed to the high amount of potassium consumed,¹⁷ which is used in the body to synthesize cortisol, a common treatment for psoriasis. Potassium supplementation has been shown to raise serum cortisol levels in patients.⁶ Although additional studies are needed to discern the significance of potassium in the vegetarian diet, both hypotheses are reasonable explanations for the observations seen in these studies.

Vitamin D and Other Nutritional Supplements

Because it is not always feasible for patients to alter their diets, many have turned to dietary supplements as an alternative method of treatment and lifestyle change. Two of the more prominently represented nutritional additives in the literature are fish oils and vitamin D.¹⁸ Supplemental vitamin D is a prohormone that can be endogenously converted to its active 1,25-dihydroxyvitamin D.¹⁹ Vitamin D plays important roles in the regulation of calcium and magnesium in the bones as well as the maturation and differentiation of keratinocytes in the skin.¹⁶ Topical vitamin D analogues are standard treatments for psoriasis, as they are used to modulate the immune system to great effect.²⁰ Some patients with psoriasis present with vitamin D insufficiency,²¹ and it stands to reason that oral supplementation may be a treatment option. There have been multiple studies assessing the efficacy of oral vitamin D for the treatment of psoriasis; however, in the only randomized and placebo-controlled trial, there was only a slight nonsignificant improvement in the group supplemented with vitamin D.²⁰ Another small, open-label study reported remarkably improved PASI scores in 9 vitamin D–supplemented, dietary calcium–restricted patients.²² The lack of recent, large-sample studies makes it hard to draw notable conclusions from these studies.

The polyunsaturated fatty acids found in fish oils also have been considered as a treatment option for psoriasis.²³ Millsop et al²⁰ conducted an analysis of the literature reviewing the efficacy of fish oil in the treatment of psoriasis. Twelve of 15 compiled trials showed an improvement in psoriasis, ranging from slight improvements from baseline levels of the disease to statistically significant decreases in PASI scores (P<.05). It is notable that the amount of fish oil given in these studies varied widely, but the amount given did not necessarily correlate with strength of impact.²⁰ For example, Mayser et al,²⁴ Bittiner et al,²⁵ and Grimminger et al²⁶ each performed prospective, double-blind studies with docosahexaenoic acid and eicosapentaenoic acid (the omega-3 fatty acids found in fish oils), and all 3 studies saw improvements in the omega-3–treated group vs the control group. The doses of the oils, however, ranged from as low as 1.2 and 1.8 g daily of docosahexaenoic acid and eicosapentaenoic acid, respectively, to 4.2 g daily of each fatty acid.^24-26

Studies also have shown little to no improvement in the use of fish oil to treat psoriasis. One such study was conducted by Soyland et al²⁷ in 1993 in Norway. Utilizing a prospective, double-blind, placebo-controlled design over 4 months on 145 patients with moderate to severe psoriasis, researchers evaluated the treatment effectiveness via PASI scores; subjective reports from the patients; clinical manifestations; and factors such as cellular infiltration, desquamation, and redness. The results were mixed, with the placebo (corn oil) group having less redness and cellular desquamation and the fish oil group showing less cellular infiltration. In the other categories, there was no significant difference between the 2 groups, and researchers concluded there was no significant benefit to treating psoriasis using fish oil vs corn oil.²⁷ As with many of the other diets, there have been no recent, large-scale studies performed on the effect of fish oil supplementation on psoriasis; however, of the studies we reviewed, none showed fish oil supplementation to have a significant negative impact on psoriasis.

Conclusion

Dietary modifications have a complex multifactorial effect on psoriasis, often dependent on the variations of psoriasis and the lifestyle of the patient, including level of exercise, activities such as smoking and drinking, and genetic susceptibilities to conditions such as obesity. Thus, it is difficult for one diet to have a significant impact on psoriasis symptoms that applies to the majority of individuals. However, it appears that certain foods or nutritional supplements can be modified from all diets for general improvement. Foods with systemic anti-inflammatory effects, such as olive oil and fish oil, seem to be beneficial in treating psoriasis. As an extension, a gluten-free diet may help psoriasis patients with celiac disease by reducing the inflammatory environment of the body. On the opposite side of the spectrum, proinflammatory foods such as dietary fat and alcohol should be avoided.²⁸

In general, larger and more recent population-based studies are needed to add to the literature on this subject. Nationwide voluntary web-based surveys such as the NutriNet-Santé study in France may be one way to quickly amass large quantities of data (ClinicalTrials.gov Identifier NCT03335644). Participants are recruited through multimedia campaigns and return online questionnaires annually for 1 decade. A subset of participants also contributes biologic samples and participates in clinical examinations. This type of data gathering would capture many variables, provide a large sample size, and perhaps shed light on regional differences in diet and lifestyle that could then be targeted with treatments.

Psoriasis is a chronic cutaneous disease associated with immune-mediated inflammation. The disease has a complex etiology, with factors such as genetics, smoking, alcohol use, diet, and stress all believed to be implicated in its appearance and severity. Specific factors, including increased body mass index and weight gain, have been associated with a higher prevalence of psoriasis and are risk factors for the disease. Because psoriasis varies in severity and incidence, patients often can experience a substantial negative impact on their quality of life, with increased incidences of anxiety and depression.¹ Because diet is an accessible and controllable variable, many patients choose to alter their diets to help relieve symptoms of the disease. This article aims to review and summarize the existing literature for possible relationships and correlations between diet and psoriasis.

Because diet is a factor contributing to psoriasis, it is a lifestyle change that patients often make. In a 2017 survey of 1206 patients with psoriasis, 86% reported modifying their diets.² Furthermore, when patients were compared with control individuals of the same sex and of similar age, it was shown that those with psoriasis consumed statistically significant lower amounts of sugar, whole-grain fiber, dairy products, and calcium (P<.001). The survey also found that patient diets included significantly more fruits, vegetables, and legumes (P<.01). Although no single diet was adhered to by patients, 40% did report attempting a specialized diet to improve their psoriasis. The most common diets were gluten free (35.6%), low carbohydrate/high protein (16.6%), and Paleolithic (11.6%). In addition to these diets, the Mediterranean diet and a vegetarian diet were both among those reported to improve psoriatic symptoms. Finally, certain foods stood out as more frequently reported to affect symptoms, particularly fish oil, fruits, vegetables, and water, which were all reported by at least 10% of respondents to positively affect their psoriasis. Reductions in consumption of alcohol, gluten, nightshades, and junk foods were associated with skin improvements in at least 50% of patients.² These baseline differences in diet informed our search of the literature and showed that dietary changes can serve as an important adjunct to treatment for many patients.

Mediterranean Diet

The Mediterranean diet consists of a high amount of fruits, vegetables, nuts and legumes, cereals, and olive oil, while restricting consumption of red meats, dairy products, and alcohol (besides red wine) at meals.³ Adherence to the diet has been associated with a reduced risk for cardiovascular diseases,⁴ rheumatoid arthritis, and Crohn disease,³ among others, possibly because the diet contains a high proportion and variety of foods that contain antioxidants and anti-inflammatory compounds, including the monounsaturated fatty acids (MUFAs) in olive oil and the polyphenols in fruits and vegetables. Consumption of both MUFAs and highly anti-inflammatory nutrients has been associated with reduced prevalence of risk factors for chronic inflammatory diseases, and consumption levels of MUFAs in particular have been reported to be a predictive factor in psoriasis severity.³

Recent studies have tried to quantify an association between consumption of the Mediterranean diet and psoriasis. One cross-sectional study in 2015 evaluated 62 patients with psoriasis for their adherence to the Mediterranean diet and psoriasis severity.⁴ Utilizing a 14-question evaluation, the study found that patients with a higher severity of psoriasis, as evaluated by a psoriasis area and severity index (PASI) score and C-reactive protein levels, had a lower adherence to the diet. Notably, consumption of extra-virgin olive oil was found to be an independent predictor of PASI score, and consumption of fish was an independent predictor of C-reactive protein levels.⁴

A second cross-sectional questionnaire study found similar results in a larger population of 3557 patients. The same association between patients with severe psoriasis and low levels of adherence to the Mediterranean diet was reported.³ Although neither study showed a causal relationship between the diet and psoriasis severity, both did report the potential impacts of proinflammatory and anti-inflammatory foods. General foods and nutrients listed by the studies as having anti-inflammatory properties include MUFAs; fish; vitamins A, C, D, and E; and omega-3 fatty acids.³ Because of the large number of confounding factors in dietary studies that rely on questionnaires, it is hard to definitively label the Mediterranean diet as beneficial topsoriasis. However, individual components of the diet may be used as predictors of psoriasis severity, and the diet itself may be used in tandem with other treatments for psoriasis.

Gluten-Free Diet

Celiac disease is an inflammatory enteropathy caused by an immune reaction to the protein gliadin, which is found in foods containing gluten, such as wheat.⁵ Immune system assault on the intestinal enterocytes leads to the stripping away of villi, negatively affecting nutrient absorption. Multiple studies have reported an association between having psoriasis and having celiac disease as well as the reverse, including a 3-fold increased risk of celiac disease for patients with psoriasis in a 2017 meta-analysis.⁶ Even if patients with psoriasis did not have celiac disease, studies have found that a notable percentage of patients with psoriasis have elevated antigliadin IgA antibody levels.⁷ Many hypotheses have been proposed to explain this association. One article suggested that the malabsorption associated with celiac disease predisposes patients to vitamin D deficiency, which is a contributing risk factor for psoriasis.⁸ Other explanations involve common immune cells involved in the response to both diseases and a shared genetic background between the 2 diseases.⁸ As a gluten-free diet is standard for patients with celiac disease, it stands to reason that IgA could be used as a serum biomarker for patients who also could see improvements by adopting the diet.

This result could help explain the proportion of respondents to the 2017 survey who experienced improvements to their psoriasis if the gluten-free diet was in fact not triggering the inflammatory effects that a regular diet would, which also may help to explain the mixed results that the gluten-free diet has had as a treatment for psoriasis. One 3-month study of patients who were positive for antigliadin antibodies found that the majority (82%) experienced a decrease in antibody levels and affected skin area after following a gluten-free diet. Only half the patients had been diagnosed with celiac disease prior to the study, lending credibility to the idea that antigliadin antibody could be used as a marker for patients with psoriasis who would benefit from a gluten-free diet.⁹ Other case studies have reported no improvement of psoriasis following implementation of a gluten-free diet,¹⁰ despite the patients having elevated gliadin antibodies or celiac disease. More studies are required to discern the exact nature of the benefits of a gluten-free diet on psoriasis; however, it does serve as a promising option for patients with both psoriasis and celiac disease.

Ketogenic Diet

As obesity and weight gain are factors associated with psoriasis, some patients turn to diets that restrict calories with the goal of losing weight to improve their symptoms. One 2015 case report studied a patient who restored her response to systemic treatment of psoriasis following an intensive 4-week, calorie-restricted ketogenic diet.¹¹ The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet. Animal studies have shown the diet to have anti-inflammatory effects, including lowering levels of proinflammatory cytokines and reduced fever.¹² In the 2015 case report, the rapid and consistent weight loss experienced by the patient because of the ketogenic diet was thought to be the cause of the restoration of treatment effectiveness,¹¹ which is interesting, since the role of the ketogenic diet was not to supplement any deficiencies but to move the patient to a physiologic state that was once again receptive to treatment. This finding suggests that a variety of diets could improve psoriasis symptoms, so long as they do not cause inflammation or reduce overall body mass. One study of patients on a calorie-restricted diet over 8 weeks did see a trend of patients on the diet showing improvement in both their PASI scores and Dermatology Life Quality Index, though the improvement was not statistically significant.¹³ To determine if the ketogenic diet has a significant association with psoriasis improvement, controlled, large-population studies should be performed in the future with age, sex, and weight-matched controls, which may be difficult to do. Further studies looking at the association between weight loss and psoriasis also could be another direction.

Vegetarian Diet

Both vegetarian and vegan diets have been evaluated for their efficacy in relieving symptoms of chronic inflammatory disorders. Although the 2 diets are similar in avoiding consumption of meat, fish, and poultry, vegan diets often have additional food restrictions, including avoiding eggs, honey, and dairy products. One study noted the impact of these diets on patients with a variety of skin conditions following a period of fasting. It was observed that some patients with psoriasis saw an improvement in their symptoms during the period when they were eating a vegetarian or vegan diet, which was attributed to a return to normal levels of activity of neutrophils, extrapolated from serum levels of lactoferrin.¹⁴ Vegetarian diets have been shown to be associated with higher ratios of anti-inflammatory to proinflammatory adipokines compared to omnivorous diets,¹⁵ as well as lower expression levels of proinflammatory genes in the gut microbiota and lower expression levels of IgE.¹⁶ Perhaps the anti-inflammatory impacts of the diet affected the symptoms of psoriasis. The benefits of a vegetarian diet also have been attributed to the high amount of potassium consumed,¹⁷ which is used in the body to synthesize cortisol, a common treatment for psoriasis. Potassium supplementation has been shown to raise serum cortisol levels in patients.⁶ Although additional studies are needed to discern the significance of potassium in the vegetarian diet, both hypotheses are reasonable explanations for the observations seen in these studies.

Vitamin D and Other Nutritional Supplements

Because it is not always feasible for patients to alter their diets, many have turned to dietary supplements as an alternative method of treatment and lifestyle change. Two of the more prominently represented nutritional additives in the literature are fish oils and vitamin D.¹⁸ Supplemental vitamin D is a prohormone that can be endogenously converted to its active 1,25-dihydroxyvitamin D.¹⁹ Vitamin D plays important roles in the regulation of calcium and magnesium in the bones as well as the maturation and differentiation of keratinocytes in the skin.¹⁶ Topical vitamin D analogues are standard treatments for psoriasis, as they are used to modulate the immune system to great effect.²⁰ Some patients with psoriasis present with vitamin D insufficiency,²¹ and it stands to reason that oral supplementation may be a treatment option. There have been multiple studies assessing the efficacy of oral vitamin D for the treatment of psoriasis; however, in the only randomized and placebo-controlled trial, there was only a slight nonsignificant improvement in the group supplemented with vitamin D.²⁰ Another small, open-label study reported remarkably improved PASI scores in 9 vitamin D–supplemented, dietary calcium–restricted patients.²² The lack of recent, large-sample studies makes it hard to draw notable conclusions from these studies.

The polyunsaturated fatty acids found in fish oils also have been considered as a treatment option for psoriasis.²³ Millsop et al²⁰ conducted an analysis of the literature reviewing the efficacy of fish oil in the treatment of psoriasis. Twelve of 15 compiled trials showed an improvement in psoriasis, ranging from slight improvements from baseline levels of the disease to statistically significant decreases in PASI scores (P<.05). It is notable that the amount of fish oil given in these studies varied widely, but the amount given did not necessarily correlate with strength of impact.²⁰ For example, Mayser et al,²⁴ Bittiner et al,²⁵ and Grimminger et al²⁶ each performed prospective, double-blind studies with docosahexaenoic acid and eicosapentaenoic acid (the omega-3 fatty acids found in fish oils), and all 3 studies saw improvements in the omega-3–treated group vs the control group. The doses of the oils, however, ranged from as low as 1.2 and 1.8 g daily of docosahexaenoic acid and eicosapentaenoic acid, respectively, to 4.2 g daily of each fatty acid.^24-26

Studies also have shown little to no improvement in the use of fish oil to treat psoriasis. One such study was conducted by Soyland et al²⁷ in 1993 in Norway. Utilizing a prospective, double-blind, placebo-controlled design over 4 months on 145 patients with moderate to severe psoriasis, researchers evaluated the treatment effectiveness via PASI scores; subjective reports from the patients; clinical manifestations; and factors such as cellular infiltration, desquamation, and redness. The results were mixed, with the placebo (corn oil) group having less redness and cellular desquamation and the fish oil group showing less cellular infiltration. In the other categories, there was no significant difference between the 2 groups, and researchers concluded there was no significant benefit to treating psoriasis using fish oil vs corn oil.²⁷ As with many of the other diets, there have been no recent, large-scale studies performed on the effect of fish oil supplementation on psoriasis; however, of the studies we reviewed, none showed fish oil supplementation to have a significant negative impact on psoriasis.

Conclusion

Dietary modifications have a complex multifactorial effect on psoriasis, often dependent on the variations of psoriasis and the lifestyle of the patient, including level of exercise, activities such as smoking and drinking, and genetic susceptibilities to conditions such as obesity. Thus, it is difficult for one diet to have a significant impact on psoriasis symptoms that applies to the majority of individuals. However, it appears that certain foods or nutritional supplements can be modified from all diets for general improvement. Foods with systemic anti-inflammatory effects, such as olive oil and fish oil, seem to be beneficial in treating psoriasis. As an extension, a gluten-free diet may help psoriasis patients with celiac disease by reducing the inflammatory environment of the body. On the opposite side of the spectrum, proinflammatory foods such as dietary fat and alcohol should be avoided.²⁸

In general, larger and more recent population-based studies are needed to add to the literature on this subject. Nationwide voluntary web-based surveys such as the NutriNet-Santé study in France may be one way to quickly amass large quantities of data (ClinicalTrials.gov Identifier NCT03335644). Participants are recruited through multimedia campaigns and return online questionnaires annually for 1 decade. A subset of participants also contributes biologic samples and participates in clinical examinations. This type of data gathering would capture many variables, provide a large sample size, and perhaps shed light on regional differences in diet and lifestyle that could then be targeted with treatments.