OBG Management

Nearly one in every six women will experience chronic vulvar symptoms at some point, from ongoing itching to sensations of rawness, burning, or dyspareunia. Regrettably, clinicians generally are taught only a few possible causes for these symptoms, primarily infections such as yeast, bacterial vaginosis, herpes simplex virus, or anogenital warts. However, infections rarely produce chronic symptoms that do not respond, at least temporarily, to therapy.

In this two-part series, we focus on a total of 10 cases of vulvar symptoms, zeroing in on diagnosis and treatment. In this first part, we describe five patient scenarios illustrating the diagnosis and treatment of:

• lichen sclerosus
• vulvodynia
• lichen simplex chronicus
• lichen planus
• hidradenitis suppurativa.

In many chronic cases, more than one entity is the cause
Specific skin diseases, sensations of rawness from various external and internal irritants, neuropathy, and psychological issues are all much more common causes of chronic vulvar symptoms than infection. Moreover, most women with chronic vulvar symptoms have more than one entity producing their discomfort.

Very often, the cause of a patient’s symptoms is not clear at the first visit, with nonspecific redness or even normal skin seen on examination. Pathognomonic skin findings can be obscured by irritant contact dermatitis caused by unnecessary medications or overwashing, atrophic vaginitis, and/or rubbing and scratching. In such cases, obvious abnormalities must be eliminated and the patient reevaluated to definitively discover and treat the cause of the symptoms.

CASE 1. ANOGENITAL ITCHING AND DYSPAREUNIA
A 62-year-old woman schedules a visit to address her anogenital itching. She reports pain with scratching and has developed introital dyspareunia. On physical examination, you find a well-demarcated white plaque of thickened, crinkled skin (FIGURE 1). A wet mount shows parabasal cells and no lactobacilli.

Diagnosis: Lichen sclerosus and atrophic vagina.

Treatment: Halobetasol ointment, an ultra-potent topical corticosteroid, once or twice daily; along with estradiol cream (0.5 g intravaginally) 3 times a week.

Lichen sclerosus is a skin disease found most often on the vulva of postmenopausal women, although it also can affect prepubertal children and reproductive-age women. Lichen sclerosus is multifactorial in pathogenesis, including prominent autoimmune factors, local environmental factors, and genetic predisposition.¹

Although there is no cure for lichen sclerosus, the symptoms and clinical abnormalities usually can be well managed with ultra-potent topical corticosteroids. However, scarring and architectural changes are not reversible. Moreover, poorly controlled lichen sclerosus exhibits malignant transformation on anogenital skin in about 3% of affected patients.

The standard of care is application of an ultra-potent topical corticosteroid ointment once or twice daily until the skin texture normalizes again. The most common of such corticosteroids are clobetasol, halobetasol, and betamethasone dipropionate in an augmented vehicle (betamethasone dipropionate in the usual vehicle is only a medium-high medication in terms of potency.) One of us (L.E.) finds that some women experience irritation with generic clobetasol.

The ointment form of the selected corticosteroid is preferred, as creams are irritating to the vulva in most women because they contain more alcohols and preservatives than ointments do. The amount to be used is very small—far smaller than the pea-sized amount often suggested. By using this smaller amount, we avoid spread to the surrounding hair-bearing skin, which is at greater risk for steroid dermatitis and atrophy than the modified mucous membranes.

Related video: Lichen sclerosis: My approach to treatment Michael Baggish, MD

Even asymptomatic lichen sclerosus can progress
Most vulvologists agree that when the skin normalizes (not when symptoms subside), it is best to either decrease the frequency of application of the ultra-potent corticosteroid to two or three times a week, or to continue daily use with a lower-potency corticosteroid such as triamcinolone ointment 0.1%. Discontinuation of therapy usually results in recurrence.²

Treatment should not be based solely on symptoms, as asymptomatic lichen sclerosus can progress and cause permanent scarring and an increased risk for squamous cell carcinoma.

Although no studies have shown a decreased risk for squamous cell carcinoma with ongoing use of a corticosteroid, vulvologists have observed that malignant transformation occurs uniformly in the setting of poorly controlled lichen sclerosus. Immune dysregulation and inflammation may play an important role, so careful management to minimize inflammation may help prevent a malignancy.³

Secondary treatment choices
Secondary choices for lichen sclerosus include the topical calcineurin inhibitors tacrolimus (Protopic) and pimecrolimus (Elidel) but not testosterone, which has been shown to be ineffective. Tacrolimus and pimecrolimus are useful but often burn upon application, and they are “black-boxed” for cutaneous squamous cell carcinoma and lymphoma. Therefore, although squamous cell carcinoma associated with their use is extraordinarily uncommon, patients should be advised of these risks, particularly because lichen sclerosus already exhibits this association.

Most postmenopausal women with lichen sclerosus also exhibit hypothyroidism, so they should be monitored for this. However, thyroid function testing in 18 children showed no evidence of hypothyroidism in that age group (L.E. unpublished data).

Estrogen replacement may be advised
Postmenopausal women who have prominent introital lichen sclerosus or dyspareunia should receive estrogen replacement of some type so that there is only one cause, rather than two, for their dyspareunia, thinning, fragility, and inelasticity.

Women with well-controlled lichen sclerosus should be followed twice a year to ensure that their disease remains suppressed with ongoing therapy, and to evaluate for active disease, adverse effects of therapy, and the appearance of dysplasia or squamous cell carcinoma.

Women with lichen sclerosus occasionally experience discomfort after their clinical skin disease has cleared. These women now have developed vulvodynia triggered by their lichen sclerosus.

Related series: Vulvar Pain Syndromes—A 3-part roundtable
Part 1. Making the correct diagnosis (September 2011)
Part 2. A bounty of treatments—but not all of them proven (October 2011)
Part 3. Causes and treatment of vestibulodynia (November 2011)

CASE 2. IS IT REALLY CHRONIC YEAST INFECTION?
A 36-year-old woman consults you about her history of chronic yeast infection that manifests as introital burning, discharge, and dyspareunia. She is otherwise healthy, except for irritable bowel syndrome and fibromyalgia.

Physical examination reveals a mild patchy redness of the vestibule and surrounding modified mucous membranes (FIGURE 2). Gentle probing with a cotton swab triggers exquisite pain in the vestibule, with slight extension to the labia minora. A wet mount shows no evidence of increased white blood cells, parabasal cells, clue cells, or yeast forms. Lactobacilli are abundant.

Diagnosis: Vulvodynia, with a nearly vestibulodynia pattern.

Treatment: Venlafaxine and pelvic floor physical therapy.

Vulvodynia is a genital pain syndrome defined as sensations of chronic burning, irritation, rawness, and soreness in the absence of objective disease and infection that could explain the discomfort. Vulvodynia occurs in approximately 7% to 8% of women.⁴

Vulvodynia generally is believed to be a multifactorial symptom, occurring as a result of pelvic floor dysfunction and neuropathic pain,^5,6 with anxiety/depression issues exacerbating symptoms. Some recent studies have shown the presence of biochemical mediators of inflammation in the absence of clinical and histologic inflammation.⁷ Discomfort often is worsened by infections or the application of common irritants (creams, panty liners, soaps, some topical anesthetics). Estrogen deficiency is another common exacerbating factor.

Women tend to exhibit other pain syndromes such as chronic headaches, fibromyalgia, temperomandibular disorder, or premenstrual syndrome, as well as prominent anxiety, depression, sleep disorder, and so on.

Almost uniformly present are symptoms of pelvic floor dysfunction, such as constipation, irritable bowel syndrome, and interstitial cystitis or urinary symptoms in the absence of a urinary tract infection. These women also are frequently unusually intolerant of medications.

Classifying vulvodynia
There are two primary patterns of vulvodynia. The first and most common is vestibulodynia, formerly called vulvar vestibulitis. The term vestibulitis was eliminated to reflect the absence of clinical and histologic inflammation. Vestibulodynia refers to pain that is always limited to the vestibule. Generalized vulvodynia, however, extends beyond the vestibule, is migratory, or does not include the vestibule.

Several vulvologists have found that many patients exhibit features of both types of vulvodynia, and these patterns probably exist on a spectrum. The difference is probably unimportant in clinical practice, except that vestibulodynia can be treated with vestibulectomy.

How we manage vulvodynia
We focus on pelvic floor physical therapy and on the provision of medication for neuropathic pain, which is initiated at very small doses and gradually increased to active doses.⁸ The medications used and the ultimate doses often required include:

• amitriptyline or desipramine 150 mg
• gabapentin 600 to 1,200 mg three times daily
• venlafaxine XR 150 mg daily
• pregabalin 150 mg twice a day
• duloxetine 60 mg a day.

Compounded amitriptyline 2% with baclofen 2% cream applied three times daily is beneficial for many patients, and topical lidocaine jelly 2% or ointment 5% (which often burns) can help provide immediate temporary relief.

Most patients require sex therapy and counseling for maximal improvement. Women with vestibulodynia in whom these therapies fail are good candidates for vestibulectomy if their pain is strictly limited to the vestibule. Fortunately, most women do not require this aggressive therapy.

Related article: Successful treatment of chronic vaginitis Robert L. Barbieri, MD (Editorial; July 2013)

CASE 3. SEVERE ITCHING DISRUPTS SLEEP
A 34-year-old patient reports excruciating itching, with disruption of daily activities and sleep. She has been treated for candidiasis on multiple occasions, but in your office her wet mount and confirmatory culture are negative. Physical examination reveals a pink, lichenified plaque with excoriation (FIGURE 3).

Diagnosis: Lichen simplex chronicus.

Treatment: Ultra-potent corticosteroid ointment applied very sparingly twice daily and covered with petroleum jelly. You also order nighttime sedation with amitriptyline to break the itch-scratch cycle. When the patient’s itching resolves and her skin clears, you taper her off the corticosteroid, warning her that recurrence is likely, and instruct her to restart the medication immediately should itching recur.

Lichen simplex chronicus (formerly called squamous hyperplasia or hyperplastic dystrophy, and also known as eczema, neurodermatitis, or localized atopic dermatitis) occurs when irritation from any cause produces itching in a predisposed person. The subsequent scratching and rubbing both produce the rash and exacerbate the irritation that drives the itching, even after the original cause is gone. The rubbing and scratching perpetuate the irritation and itching, producing the “itch-scratch” cycle.

The appearance of lichen simplex chronicus is produced by rubbing (where the skin thickens and lichenifies) or scratching (where the skin becomes red with linear erosions, called excoriations, caused by fingernails).

The initial trigger for lichen simplex chronicus often is an infection—often yeast—but overwashing, stress, sweat, heat, urine, irritating lubricants, and use of panty liners also may precipitate the itching. At the office visit, the original infection or other cause of irritation often is no longer present, and only lichen simplex chronicus can be identified.

How to treat lichen simplex chronicus
Management of lichen simplex chronicus requires very sparing application of an ultra-potent topical corticosteroid (clobetasol, halobetasol, or betamethasone dipropionate in an augmented vehicle ointment) twice daily, with the ointment covered with petroleum jelly. Care also must be taken to avoid irritants.

In addition, nighttime sedation helps to interrupt the itch-scratch cycle by preventing rubbing during sleep.

When the skin appears normal and itching has resolved, taper the medication down or off, warning the patient that recurrence is common with any future irritation.

Restart therapy immediately upon recurrence to prevent lichenification and chronic problems.

Second-line medications include calcineurin inhibitors (tacrolimus or pimecrolimus). Although these agents do not contribute to atrophy, they are less effective than topical corticosteroids,⁹ cost more, and can cause burning upon application.

Unlike lichen sclerosus, lichen simplex chronicus does not always recur upon cessation of treatment, and there is no need for concern about an increased risk of malignancy or significant scarring.

Related article: New treatment option for vulvar and vaginal atrophy  Andrew M. Kaunitz, MD (News for your Practice; May 2013)

CASE 4. ORAL AND VULVAR INVOLVEMENT
A 73-year-old patient seeks your help in alleviating longstanding introital itching and rawness, with dyspareunia. She has tried topical estradiol cream intravaginally three times weekly in combination with weekly fluconazole, to no avail.

Physical examination reveals deep red patches and erosions of the vestibule, with complete resorption of the labia minora (FIGURE 4). Patchy redness of the vagina is apparent as well, so you examine the patient’s mouth and find deep redness of the gingivae and erosions of the buccal mucosae, with surrounding white, lacy papules. A wet mount shows a marked increase in lymphocytes and parabasal cells, with a pH of more than 7.

Diagnosis: After correlating the vulvar and oral findings, you make a diagnosis of lichen planus.

Treatment: You initiate halobetasol ointment twice daily, to be applied to the vulva. You also continue vaginal estradiol cream but add hydrocortisone acetate 200 mg compounded vaginal suppositories nightly, as well as clobetasol gel to be applied to oral lesions three times a day. You follow the patient closely for secondary yeast of the mouth and vagina.

Erosive multimucosal lichen planus is a disease of cell-mediated immunity that overwhelmingly affects menopausal women. The most common surfaces involved are the mouth, vagina, rectal mucosa, and vulva; usually, at least two surfaces are affected. The esophagus, extra-auditory canals, nasal mucosa, and eyes also can be involved. Dry, extragenital skin usually is not affected in the setting of erosive vulvovaginal lichen planus.

Vulvar lichen planus most often is controlled with ultra-potent topical corticosteroids (again, clobetasol, halobetasol, or betamethasone dipropionate in an augmented vehicle), but other mucosal surfaces often are more difficult to manage. Although there is no definitive cure for this condition, careful local care, estrogen replacement, and suppression of oral and vulvovaginal candidiasis usually provide relief.

Calcineurin inhibitors (tacrolimus, pimecrolimus) sometimes are useful in patients who improve only partially after treatment with a topical corticosteroid, provided burning with application is tolerable.¹⁰ Systemic immunosuppressants such as hydroxychloroquine, methotrexate, mycophenolate mofetil, azathioprine, cyclosporine, cyclophosphamide, and tumor necrosis factor (TNF) alpha blockers (etanercept, adalimumab, infliximab), as well as oral retinoids, can be added for more recalcitrant disease.¹¹

How to manage disease that affects the vagina
When the vagina is involved in lichen planus, treatment is important to prevent scarring, as well as rawness and pain from irritant contact dermatitis caused by purulent vaginal secretions. Occasionally, a 25-mg hydrocortisone acetate rectal suppository inserted into the vagina nightly improves vaginal lichen planus, but sometimes more potent suppositories, such as doses of 100 to 200 mg, may be compounded. Dilators should be inserted daily to prevent vaginal synechiae.

Oral involvement requires targeted treatment
The mouth is almost always involved in lichen planus. If a dermatologist is not involved in patient care, a prescription for dexamethasone/nystatin elixir (50:50) (5 mL swish, hold, and spit four times daily) can improve oral symptoms remarkably. Alternatively, clobetasol gel applied to affected areas of the mouth three or four times daily can be helpful. Secondary yeast of the vagina and mouth are common with the use of topical corticosteroids.

Careful clinical follow-up is advised
Like uncontrolled lichen sclerosus, erosive lichen planus of the vulva produces scarring and sometimes eventuates into squamous cell carcinoma. Therefore, careful clinical surveillance is warranted. And therapy must be continued to prevent recurrence of lichen planus (as it must be for lichen sclerosus), scarring, and to decrease the risk of squamous cell carcinoma. And like lichen sclerosus, lichen planus sometimes triggers vulvodynia.

CASE 5. MULTIPLE BOILS IN THE GROIN
A 31-year-old morbidly obese African American woman comes to your office with continually evolving boils in the groin. A culture shows Bacterioides spp, Escherichia coli, and Peptococcus spp. In the past, multiple courses of various antibiotics have provided only modest relief.

Physical examination reveals fluctuant nodules, scars, and draining sinus tracts of the hair-bearing vulva and crural crease (FIGURE 5). The axillae are clear.

Diagnosis: Hidradenitis suppurativa.

Treatment: The patient begins taking minocycline 100 mg twice daily. Because she is a smoker, you refer her to an aggressive primary care provider for smoking cessation and weight loss management.

Three months later, the patient is developing only about two nodules a month, managed by early intralesional injections of triamcinolone acetonide.

Hidradenitis suppurativa is sometimes called inverse acne because the underlying pathogenesis is similar to cystic acne. Follicular plugging with keratin debris occurs, with additional keratin, sebaceous material, and normal skin bacteria trapped below the occlusion and distending the follicle. As the follicle wall stretches, thins, and allows for leakage of keratin debris into surrounding dermis, a brisk foreign-body response ­produces a noninfectious abscess.

Hidradenitis suppurativa affects more than 2% of the population.¹² It appears only in areas of the body that contain apocrine glands and in individuals who have double- or triple-outlet follicles that predispose them to follicular occlusion. Therefore, this disease has a genetic component.

Other risk factors include male sex, African genetic background, obesity, and smoking. The prevalence of metabolic syndrome is significantly higher in individuals with hidradenitis suppurativa than in the general population.¹³

Recommended management
Treatments include:

• chronic antibiotics with nonspecific anti-inflammatory activity (tetracyclines, erythromycin, clindamycin, and trimethoprim-sulfamethoxazole)
• intralesional injection of corticosteroids for early nodules (which often aborts their development)
• TNF alpha blockers (etanercept, adalimumab, infliximab)^14–16
• surgical removal of affected skin—the definitive therapy.

Note, however, that anogenital hidradenitis often is too extensive for surgery to be practical. In patients who have localized hidradenitis, primary excision is an excellent early therapy, provided the patient is advised that recurrence may occur in apocrine-containing nearby skin. Aggressive curettage of the roof of the cysts has been performed by some clinicians with good response.

Don’t overlook adjuvant approaches
Smoking cessation and weight loss often are useful.

Other therapies backed by anecdotal evidence include oral contraceptives or spironolactone for their anti-androgen effect, as well as metformin, a more recently studied agent.

Local care with antibacterial soaps and topical antibiotics may be useful for some women.

MORE CASES TO COME
In Part 2 of this series, which will appear in the June 2014 issue of OBG Management, we will discuss the following cases:

• atrophic vagina and atrophic vaginitis
• contact dermatitis
• vulvar aphthae
• desquamative inflammatory vaginitis
• psoriasis.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article. Send your letter to: [email protected] Please include the city and state in which you practice. 

Nearly one in every six women will experience chronic vulvar symptoms at some point, from ongoing itching to sensations of rawness, burning, or dyspareunia. Regrettably, clinicians generally are taught only a few possible causes for these symptoms, primarily infections such as yeast, bacterial vaginosis, herpes simplex virus, or anogenital warts. However, infections rarely produce chronic symptoms that do not respond, at least temporarily, to therapy.

In this two-part series, we focus on a total of 10 cases of vulvar symptoms, zeroing in on diagnosis and treatment. In this first part, we describe five patient scenarios illustrating the diagnosis and treatment of:

• lichen sclerosus
• vulvodynia
• lichen simplex chronicus
• lichen planus
• hidradenitis suppurativa.

In many chronic cases, more than one entity is the cause
Specific skin diseases, sensations of rawness from various external and internal irritants, neuropathy, and psychological issues are all much more common causes of chronic vulvar symptoms than infection. Moreover, most women with chronic vulvar symptoms have more than one entity producing their discomfort.

Very often, the cause of a patient’s symptoms is not clear at the first visit, with nonspecific redness or even normal skin seen on examination. Pathognomonic skin findings can be obscured by irritant contact dermatitis caused by unnecessary medications or overwashing, atrophic vaginitis, and/or rubbing and scratching. In such cases, obvious abnormalities must be eliminated and the patient reevaluated to definitively discover and treat the cause of the symptoms.

CASE 1. ANOGENITAL ITCHING AND DYSPAREUNIA
A 62-year-old woman schedules a visit to address her anogenital itching. She reports pain with scratching and has developed introital dyspareunia. On physical examination, you find a well-demarcated white plaque of thickened, crinkled skin (FIGURE 1). A wet mount shows parabasal cells and no lactobacilli.

Diagnosis: Lichen sclerosus and atrophic vagina.

Treatment: Halobetasol ointment, an ultra-potent topical corticosteroid, once or twice daily; along with estradiol cream (0.5 g intravaginally) 3 times a week.

Lichen sclerosus is a skin disease found most often on the vulva of postmenopausal women, although it also can affect prepubertal children and reproductive-age women. Lichen sclerosus is multifactorial in pathogenesis, including prominent autoimmune factors, local environmental factors, and genetic predisposition.¹

Although there is no cure for lichen sclerosus, the symptoms and clinical abnormalities usually can be well managed with ultra-potent topical corticosteroids. However, scarring and architectural changes are not reversible. Moreover, poorly controlled lichen sclerosus exhibits malignant transformation on anogenital skin in about 3% of affected patients.

The standard of care is application of an ultra-potent topical corticosteroid ointment once or twice daily until the skin texture normalizes again. The most common of such corticosteroids are clobetasol, halobetasol, and betamethasone dipropionate in an augmented vehicle (betamethasone dipropionate in the usual vehicle is only a medium-high medication in terms of potency.) One of us (L.E.) finds that some women experience irritation with generic clobetasol.

The ointment form of the selected corticosteroid is preferred, as creams are irritating to the vulva in most women because they contain more alcohols and preservatives than ointments do. The amount to be used is very small—far smaller than the pea-sized amount often suggested. By using this smaller amount, we avoid spread to the surrounding hair-bearing skin, which is at greater risk for steroid dermatitis and atrophy than the modified mucous membranes.

Related video: Lichen sclerosis: My approach to treatment Michael Baggish, MD

Even asymptomatic lichen sclerosus can progress
Most vulvologists agree that when the skin normalizes (not when symptoms subside), it is best to either decrease the frequency of application of the ultra-potent corticosteroid to two or three times a week, or to continue daily use with a lower-potency corticosteroid such as triamcinolone ointment 0.1%. Discontinuation of therapy usually results in recurrence.²

Treatment should not be based solely on symptoms, as asymptomatic lichen sclerosus can progress and cause permanent scarring and an increased risk for squamous cell carcinoma.

Although no studies have shown a decreased risk for squamous cell carcinoma with ongoing use of a corticosteroid, vulvologists have observed that malignant transformation occurs uniformly in the setting of poorly controlled lichen sclerosus. Immune dysregulation and inflammation may play an important role, so careful management to minimize inflammation may help prevent a malignancy.³

Secondary treatment choices
Secondary choices for lichen sclerosus include the topical calcineurin inhibitors tacrolimus (Protopic) and pimecrolimus (Elidel) but not testosterone, which has been shown to be ineffective. Tacrolimus and pimecrolimus are useful but often burn upon application, and they are “black-boxed” for cutaneous squamous cell carcinoma and lymphoma. Therefore, although squamous cell carcinoma associated with their use is extraordinarily uncommon, patients should be advised of these risks, particularly because lichen sclerosus already exhibits this association.

Most postmenopausal women with lichen sclerosus also exhibit hypothyroidism, so they should be monitored for this. However, thyroid function testing in 18 children showed no evidence of hypothyroidism in that age group (L.E. unpublished data).

Estrogen replacement may be advised
Postmenopausal women who have prominent introital lichen sclerosus or dyspareunia should receive estrogen replacement of some type so that there is only one cause, rather than two, for their dyspareunia, thinning, fragility, and inelasticity.

Women with well-controlled lichen sclerosus should be followed twice a year to ensure that their disease remains suppressed with ongoing therapy, and to evaluate for active disease, adverse effects of therapy, and the appearance of dysplasia or squamous cell carcinoma.

Women with lichen sclerosus occasionally experience discomfort after their clinical skin disease has cleared. These women now have developed vulvodynia triggered by their lichen sclerosus.

Related series: Vulvar Pain Syndromes—A 3-part roundtable
Part 1. Making the correct diagnosis (September 2011)
Part 2. A bounty of treatments—but not all of them proven (October 2011)
Part 3. Causes and treatment of vestibulodynia (November 2011)

CASE 2. IS IT REALLY CHRONIC YEAST INFECTION?
A 36-year-old woman consults you about her history of chronic yeast infection that manifests as introital burning, discharge, and dyspareunia. She is otherwise healthy, except for irritable bowel syndrome and fibromyalgia.

Physical examination reveals a mild patchy redness of the vestibule and surrounding modified mucous membranes (FIGURE 2). Gentle probing with a cotton swab triggers exquisite pain in the vestibule, with slight extension to the labia minora. A wet mount shows no evidence of increased white blood cells, parabasal cells, clue cells, or yeast forms. Lactobacilli are abundant.

Diagnosis: Vulvodynia, with a nearly vestibulodynia pattern.

Treatment: Venlafaxine and pelvic floor physical therapy.

Vulvodynia is a genital pain syndrome defined as sensations of chronic burning, irritation, rawness, and soreness in the absence of objective disease and infection that could explain the discomfort. Vulvodynia occurs in approximately 7% to 8% of women.⁴

Vulvodynia generally is believed to be a multifactorial symptom, occurring as a result of pelvic floor dysfunction and neuropathic pain,^5,6 with anxiety/depression issues exacerbating symptoms. Some recent studies have shown the presence of biochemical mediators of inflammation in the absence of clinical and histologic inflammation.⁷ Discomfort often is worsened by infections or the application of common irritants (creams, panty liners, soaps, some topical anesthetics). Estrogen deficiency is another common exacerbating factor.

Women tend to exhibit other pain syndromes such as chronic headaches, fibromyalgia, temperomandibular disorder, or premenstrual syndrome, as well as prominent anxiety, depression, sleep disorder, and so on.

Almost uniformly present are symptoms of pelvic floor dysfunction, such as constipation, irritable bowel syndrome, and interstitial cystitis or urinary symptoms in the absence of a urinary tract infection. These women also are frequently unusually intolerant of medications.

Classifying vulvodynia
There are two primary patterns of vulvodynia. The first and most common is vestibulodynia, formerly called vulvar vestibulitis. The term vestibulitis was eliminated to reflect the absence of clinical and histologic inflammation. Vestibulodynia refers to pain that is always limited to the vestibule. Generalized vulvodynia, however, extends beyond the vestibule, is migratory, or does not include the vestibule.

Several vulvologists have found that many patients exhibit features of both types of vulvodynia, and these patterns probably exist on a spectrum. The difference is probably unimportant in clinical practice, except that vestibulodynia can be treated with vestibulectomy.

How we manage vulvodynia
We focus on pelvic floor physical therapy and on the provision of medication for neuropathic pain, which is initiated at very small doses and gradually increased to active doses.⁸ The medications used and the ultimate doses often required include:

• amitriptyline or desipramine 150 mg
• gabapentin 600 to 1,200 mg three times daily
• venlafaxine XR 150 mg daily
• pregabalin 150 mg twice a day
• duloxetine 60 mg a day.

Compounded amitriptyline 2% with baclofen 2% cream applied three times daily is beneficial for many patients, and topical lidocaine jelly 2% or ointment 5% (which often burns) can help provide immediate temporary relief.

Most patients require sex therapy and counseling for maximal improvement. Women with vestibulodynia in whom these therapies fail are good candidates for vestibulectomy if their pain is strictly limited to the vestibule. Fortunately, most women do not require this aggressive therapy.

Related article: Successful treatment of chronic vaginitis Robert L. Barbieri, MD (Editorial; July 2013)

CASE 3. SEVERE ITCHING DISRUPTS SLEEP
A 34-year-old patient reports excruciating itching, with disruption of daily activities and sleep. She has been treated for candidiasis on multiple occasions, but in your office her wet mount and confirmatory culture are negative. Physical examination reveals a pink, lichenified plaque with excoriation (FIGURE 3).

Diagnosis: Lichen simplex chronicus.

Treatment: Ultra-potent corticosteroid ointment applied very sparingly twice daily and covered with petroleum jelly. You also order nighttime sedation with amitriptyline to break the itch-scratch cycle. When the patient’s itching resolves and her skin clears, you taper her off the corticosteroid, warning her that recurrence is likely, and instruct her to restart the medication immediately should itching recur.

Lichen simplex chronicus (formerly called squamous hyperplasia or hyperplastic dystrophy, and also known as eczema, neurodermatitis, or localized atopic dermatitis) occurs when irritation from any cause produces itching in a predisposed person. The subsequent scratching and rubbing both produce the rash and exacerbate the irritation that drives the itching, even after the original cause is gone. The rubbing and scratching perpetuate the irritation and itching, producing the “itch-scratch” cycle.

The appearance of lichen simplex chronicus is produced by rubbing (where the skin thickens and lichenifies) or scratching (where the skin becomes red with linear erosions, called excoriations, caused by fingernails).

The initial trigger for lichen simplex chronicus often is an infection—often yeast—but overwashing, stress, sweat, heat, urine, irritating lubricants, and use of panty liners also may precipitate the itching. At the office visit, the original infection or other cause of irritation often is no longer present, and only lichen simplex chronicus can be identified.

How to treat lichen simplex chronicus
Management of lichen simplex chronicus requires very sparing application of an ultra-potent topical corticosteroid (clobetasol, halobetasol, or betamethasone dipropionate in an augmented vehicle ointment) twice daily, with the ointment covered with petroleum jelly. Care also must be taken to avoid irritants.

In addition, nighttime sedation helps to interrupt the itch-scratch cycle by preventing rubbing during sleep.

When the skin appears normal and itching has resolved, taper the medication down or off, warning the patient that recurrence is common with any future irritation.

Restart therapy immediately upon recurrence to prevent lichenification and chronic problems.

Second-line medications include calcineurin inhibitors (tacrolimus or pimecrolimus). Although these agents do not contribute to atrophy, they are less effective than topical corticosteroids,⁹ cost more, and can cause burning upon application.

Unlike lichen sclerosus, lichen simplex chronicus does not always recur upon cessation of treatment, and there is no need for concern about an increased risk of malignancy or significant scarring.

Related article: New treatment option for vulvar and vaginal atrophy  Andrew M. Kaunitz, MD (News for your Practice; May 2013)

CASE 4. ORAL AND VULVAR INVOLVEMENT
A 73-year-old patient seeks your help in alleviating longstanding introital itching and rawness, with dyspareunia. She has tried topical estradiol cream intravaginally three times weekly in combination with weekly fluconazole, to no avail.

Physical examination reveals deep red patches and erosions of the vestibule, with complete resorption of the labia minora (FIGURE 4). Patchy redness of the vagina is apparent as well, so you examine the patient’s mouth and find deep redness of the gingivae and erosions of the buccal mucosae, with surrounding white, lacy papules. A wet mount shows a marked increase in lymphocytes and parabasal cells, with a pH of more than 7.

Diagnosis: After correlating the vulvar and oral findings, you make a diagnosis of lichen planus.

Treatment: You initiate halobetasol ointment twice daily, to be applied to the vulva. You also continue vaginal estradiol cream but add hydrocortisone acetate 200 mg compounded vaginal suppositories nightly, as well as clobetasol gel to be applied to oral lesions three times a day. You follow the patient closely for secondary yeast of the mouth and vagina.

Erosive multimucosal lichen planus is a disease of cell-mediated immunity that overwhelmingly affects menopausal women. The most common surfaces involved are the mouth, vagina, rectal mucosa, and vulva; usually, at least two surfaces are affected. The esophagus, extra-auditory canals, nasal mucosa, and eyes also can be involved. Dry, extragenital skin usually is not affected in the setting of erosive vulvovaginal lichen planus.

Vulvar lichen planus most often is controlled with ultra-potent topical corticosteroids (again, clobetasol, halobetasol, or betamethasone dipropionate in an augmented vehicle), but other mucosal surfaces often are more difficult to manage. Although there is no definitive cure for this condition, careful local care, estrogen replacement, and suppression of oral and vulvovaginal candidiasis usually provide relief.

Calcineurin inhibitors (tacrolimus, pimecrolimus) sometimes are useful in patients who improve only partially after treatment with a topical corticosteroid, provided burning with application is tolerable.¹⁰ Systemic immunosuppressants such as hydroxychloroquine, methotrexate, mycophenolate mofetil, azathioprine, cyclosporine, cyclophosphamide, and tumor necrosis factor (TNF) alpha blockers (etanercept, adalimumab, infliximab), as well as oral retinoids, can be added for more recalcitrant disease.¹¹

How to manage disease that affects the vagina
When the vagina is involved in lichen planus, treatment is important to prevent scarring, as well as rawness and pain from irritant contact dermatitis caused by purulent vaginal secretions. Occasionally, a 25-mg hydrocortisone acetate rectal suppository inserted into the vagina nightly improves vaginal lichen planus, but sometimes more potent suppositories, such as doses of 100 to 200 mg, may be compounded. Dilators should be inserted daily to prevent vaginal synechiae.

Oral involvement requires targeted treatment
The mouth is almost always involved in lichen planus. If a dermatologist is not involved in patient care, a prescription for dexamethasone/nystatin elixir (50:50) (5 mL swish, hold, and spit four times daily) can improve oral symptoms remarkably. Alternatively, clobetasol gel applied to affected areas of the mouth three or four times daily can be helpful. Secondary yeast of the vagina and mouth are common with the use of topical corticosteroids.

Careful clinical follow-up is advised
Like uncontrolled lichen sclerosus, erosive lichen planus of the vulva produces scarring and sometimes eventuates into squamous cell carcinoma. Therefore, careful clinical surveillance is warranted. And therapy must be continued to prevent recurrence of lichen planus (as it must be for lichen sclerosus), scarring, and to decrease the risk of squamous cell carcinoma. And like lichen sclerosus, lichen planus sometimes triggers vulvodynia.

CASE 5. MULTIPLE BOILS IN THE GROIN
A 31-year-old morbidly obese African American woman comes to your office with continually evolving boils in the groin. A culture shows Bacterioides spp, Escherichia coli, and Peptococcus spp. In the past, multiple courses of various antibiotics have provided only modest relief.

Physical examination reveals fluctuant nodules, scars, and draining sinus tracts of the hair-bearing vulva and crural crease (FIGURE 5). The axillae are clear.

Diagnosis: Hidradenitis suppurativa.

Treatment: The patient begins taking minocycline 100 mg twice daily. Because she is a smoker, you refer her to an aggressive primary care provider for smoking cessation and weight loss management.

Three months later, the patient is developing only about two nodules a month, managed by early intralesional injections of triamcinolone acetonide.

Hidradenitis suppurativa is sometimes called inverse acne because the underlying pathogenesis is similar to cystic acne. Follicular plugging with keratin debris occurs, with additional keratin, sebaceous material, and normal skin bacteria trapped below the occlusion and distending the follicle. As the follicle wall stretches, thins, and allows for leakage of keratin debris into surrounding dermis, a brisk foreign-body response ­produces a noninfectious abscess.

Hidradenitis suppurativa affects more than 2% of the population.¹² It appears only in areas of the body that contain apocrine glands and in individuals who have double- or triple-outlet follicles that predispose them to follicular occlusion. Therefore, this disease has a genetic component.

Other risk factors include male sex, African genetic background, obesity, and smoking. The prevalence of metabolic syndrome is significantly higher in individuals with hidradenitis suppurativa than in the general population.¹³

Recommended management
Treatments include:

• chronic antibiotics with nonspecific anti-inflammatory activity (tetracyclines, erythromycin, clindamycin, and trimethoprim-sulfamethoxazole)
• intralesional injection of corticosteroids for early nodules (which often aborts their development)
• TNF alpha blockers (etanercept, adalimumab, infliximab)^14–16
• surgical removal of affected skin—the definitive therapy.

Note, however, that anogenital hidradenitis often is too extensive for surgery to be practical. In patients who have localized hidradenitis, primary excision is an excellent early therapy, provided the patient is advised that recurrence may occur in apocrine-containing nearby skin. Aggressive curettage of the roof of the cysts has been performed by some clinicians with good response.

Don’t overlook adjuvant approaches
Smoking cessation and weight loss often are useful.

Other therapies backed by anecdotal evidence include oral contraceptives or spironolactone for their anti-androgen effect, as well as metformin, a more recently studied agent.

Local care with antibacterial soaps and topical antibiotics may be useful for some women.

MORE CASES TO COME
In Part 2 of this series, which will appear in the June 2014 issue of OBG Management, we will discuss the following cases:

• atrophic vagina and atrophic vaginitis
• contact dermatitis
• vulvar aphthae
• desquamative inflammatory vaginitis
• psoriasis.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article. Send your letter to: [email protected] Please include the city and state in which you practice. 

Nearly one in every six women will experience chronic vulvar symptoms at some point, from ongoing itching to sensations of rawness, burning, or dyspareunia. Regrettably, clinicians generally are taught only a few possible causes for these symptoms, primarily infections such as yeast, bacterial vaginosis, herpes simplex virus, or anogenital warts. However, infections rarely produce chronic symptoms that do not respond, at least temporarily, to therapy.

In this two-part series, we focus on a total of 10 cases of vulvar symptoms, zeroing in on diagnosis and treatment. In this first part, we describe five patient scenarios illustrating the diagnosis and treatment of:

• lichen sclerosus
• vulvodynia
• lichen simplex chronicus
• lichen planus
• hidradenitis suppurativa.

In many chronic cases, more than one entity is the cause
Specific skin diseases, sensations of rawness from various external and internal irritants, neuropathy, and psychological issues are all much more common causes of chronic vulvar symptoms than infection. Moreover, most women with chronic vulvar symptoms have more than one entity producing their discomfort.

Very often, the cause of a patient’s symptoms is not clear at the first visit, with nonspecific redness or even normal skin seen on examination. Pathognomonic skin findings can be obscured by irritant contact dermatitis caused by unnecessary medications or overwashing, atrophic vaginitis, and/or rubbing and scratching. In such cases, obvious abnormalities must be eliminated and the patient reevaluated to definitively discover and treat the cause of the symptoms.

CASE 1. ANOGENITAL ITCHING AND DYSPAREUNIA
A 62-year-old woman schedules a visit to address her anogenital itching. She reports pain with scratching and has developed introital dyspareunia. On physical examination, you find a well-demarcated white plaque of thickened, crinkled skin (FIGURE 1). A wet mount shows parabasal cells and no lactobacilli.

Diagnosis: Lichen sclerosus and atrophic vagina.

Treatment: Halobetasol ointment, an ultra-potent topical corticosteroid, once or twice daily; along with estradiol cream (0.5 g intravaginally) 3 times a week.

Lichen sclerosus is a skin disease found most often on the vulva of postmenopausal women, although it also can affect prepubertal children and reproductive-age women. Lichen sclerosus is multifactorial in pathogenesis, including prominent autoimmune factors, local environmental factors, and genetic predisposition.¹

Although there is no cure for lichen sclerosus, the symptoms and clinical abnormalities usually can be well managed with ultra-potent topical corticosteroids. However, scarring and architectural changes are not reversible. Moreover, poorly controlled lichen sclerosus exhibits malignant transformation on anogenital skin in about 3% of affected patients.

The standard of care is application of an ultra-potent topical corticosteroid ointment once or twice daily until the skin texture normalizes again. The most common of such corticosteroids are clobetasol, halobetasol, and betamethasone dipropionate in an augmented vehicle (betamethasone dipropionate in the usual vehicle is only a medium-high medication in terms of potency.) One of us (L.E.) finds that some women experience irritation with generic clobetasol.

The ointment form of the selected corticosteroid is preferred, as creams are irritating to the vulva in most women because they contain more alcohols and preservatives than ointments do. The amount to be used is very small—far smaller than the pea-sized amount often suggested. By using this smaller amount, we avoid spread to the surrounding hair-bearing skin, which is at greater risk for steroid dermatitis and atrophy than the modified mucous membranes.

Related video: Lichen sclerosis: My approach to treatment Michael Baggish, MD

Even asymptomatic lichen sclerosus can progress
Most vulvologists agree that when the skin normalizes (not when symptoms subside), it is best to either decrease the frequency of application of the ultra-potent corticosteroid to two or three times a week, or to continue daily use with a lower-potency corticosteroid such as triamcinolone ointment 0.1%. Discontinuation of therapy usually results in recurrence.²

Treatment should not be based solely on symptoms, as asymptomatic lichen sclerosus can progress and cause permanent scarring and an increased risk for squamous cell carcinoma.

Although no studies have shown a decreased risk for squamous cell carcinoma with ongoing use of a corticosteroid, vulvologists have observed that malignant transformation occurs uniformly in the setting of poorly controlled lichen sclerosus. Immune dysregulation and inflammation may play an important role, so careful management to minimize inflammation may help prevent a malignancy.³

Secondary treatment choices
Secondary choices for lichen sclerosus include the topical calcineurin inhibitors tacrolimus (Protopic) and pimecrolimus (Elidel) but not testosterone, which has been shown to be ineffective. Tacrolimus and pimecrolimus are useful but often burn upon application, and they are “black-boxed” for cutaneous squamous cell carcinoma and lymphoma. Therefore, although squamous cell carcinoma associated with their use is extraordinarily uncommon, patients should be advised of these risks, particularly because lichen sclerosus already exhibits this association.

Most postmenopausal women with lichen sclerosus also exhibit hypothyroidism, so they should be monitored for this. However, thyroid function testing in 18 children showed no evidence of hypothyroidism in that age group (L.E. unpublished data).

Estrogen replacement may be advised
Postmenopausal women who have prominent introital lichen sclerosus or dyspareunia should receive estrogen replacement of some type so that there is only one cause, rather than two, for their dyspareunia, thinning, fragility, and inelasticity.

Women with well-controlled lichen sclerosus should be followed twice a year to ensure that their disease remains suppressed with ongoing therapy, and to evaluate for active disease, adverse effects of therapy, and the appearance of dysplasia or squamous cell carcinoma.

Women with lichen sclerosus occasionally experience discomfort after their clinical skin disease has cleared. These women now have developed vulvodynia triggered by their lichen sclerosus.

Related series: Vulvar Pain Syndromes—A 3-part roundtable
Part 1. Making the correct diagnosis (September 2011)
Part 2. A bounty of treatments—but not all of them proven (October 2011)
Part 3. Causes and treatment of vestibulodynia (November 2011)

CASE 2. IS IT REALLY CHRONIC YEAST INFECTION?
A 36-year-old woman consults you about her history of chronic yeast infection that manifests as introital burning, discharge, and dyspareunia. She is otherwise healthy, except for irritable bowel syndrome and fibromyalgia.

Physical examination reveals a mild patchy redness of the vestibule and surrounding modified mucous membranes (FIGURE 2). Gentle probing with a cotton swab triggers exquisite pain in the vestibule, with slight extension to the labia minora. A wet mount shows no evidence of increased white blood cells, parabasal cells, clue cells, or yeast forms. Lactobacilli are abundant.

Diagnosis: Vulvodynia, with a nearly vestibulodynia pattern.

Treatment: Venlafaxine and pelvic floor physical therapy.

Vulvodynia is a genital pain syndrome defined as sensations of chronic burning, irritation, rawness, and soreness in the absence of objective disease and infection that could explain the discomfort. Vulvodynia occurs in approximately 7% to 8% of women.⁴

Vulvodynia generally is believed to be a multifactorial symptom, occurring as a result of pelvic floor dysfunction and neuropathic pain,^5,6 with anxiety/depression issues exacerbating symptoms. Some recent studies have shown the presence of biochemical mediators of inflammation in the absence of clinical and histologic inflammation.⁷ Discomfort often is worsened by infections or the application of common irritants (creams, panty liners, soaps, some topical anesthetics). Estrogen deficiency is another common exacerbating factor.

Women tend to exhibit other pain syndromes such as chronic headaches, fibromyalgia, temperomandibular disorder, or premenstrual syndrome, as well as prominent anxiety, depression, sleep disorder, and so on.

Almost uniformly present are symptoms of pelvic floor dysfunction, such as constipation, irritable bowel syndrome, and interstitial cystitis or urinary symptoms in the absence of a urinary tract infection. These women also are frequently unusually intolerant of medications.

Classifying vulvodynia
There are two primary patterns of vulvodynia. The first and most common is vestibulodynia, formerly called vulvar vestibulitis. The term vestibulitis was eliminated to reflect the absence of clinical and histologic inflammation. Vestibulodynia refers to pain that is always limited to the vestibule. Generalized vulvodynia, however, extends beyond the vestibule, is migratory, or does not include the vestibule.

Several vulvologists have found that many patients exhibit features of both types of vulvodynia, and these patterns probably exist on a spectrum. The difference is probably unimportant in clinical practice, except that vestibulodynia can be treated with vestibulectomy.

How we manage vulvodynia
We focus on pelvic floor physical therapy and on the provision of medication for neuropathic pain, which is initiated at very small doses and gradually increased to active doses.⁸ The medications used and the ultimate doses often required include:

• amitriptyline or desipramine 150 mg
• gabapentin 600 to 1,200 mg three times daily
• venlafaxine XR 150 mg daily
• pregabalin 150 mg twice a day
• duloxetine 60 mg a day.

Compounded amitriptyline 2% with baclofen 2% cream applied three times daily is beneficial for many patients, and topical lidocaine jelly 2% or ointment 5% (which often burns) can help provide immediate temporary relief.

Most patients require sex therapy and counseling for maximal improvement. Women with vestibulodynia in whom these therapies fail are good candidates for vestibulectomy if their pain is strictly limited to the vestibule. Fortunately, most women do not require this aggressive therapy.

Related article: Successful treatment of chronic vaginitis Robert L. Barbieri, MD (Editorial; July 2013)

CASE 3. SEVERE ITCHING DISRUPTS SLEEP
A 34-year-old patient reports excruciating itching, with disruption of daily activities and sleep. She has been treated for candidiasis on multiple occasions, but in your office her wet mount and confirmatory culture are negative. Physical examination reveals a pink, lichenified plaque with excoriation (FIGURE 3).

Diagnosis: Lichen simplex chronicus.

Treatment: Ultra-potent corticosteroid ointment applied very sparingly twice daily and covered with petroleum jelly. You also order nighttime sedation with amitriptyline to break the itch-scratch cycle. When the patient’s itching resolves and her skin clears, you taper her off the corticosteroid, warning her that recurrence is likely, and instruct her to restart the medication immediately should itching recur.

Lichen simplex chronicus (formerly called squamous hyperplasia or hyperplastic dystrophy, and also known as eczema, neurodermatitis, or localized atopic dermatitis) occurs when irritation from any cause produces itching in a predisposed person. The subsequent scratching and rubbing both produce the rash and exacerbate the irritation that drives the itching, even after the original cause is gone. The rubbing and scratching perpetuate the irritation and itching, producing the “itch-scratch” cycle.

The appearance of lichen simplex chronicus is produced by rubbing (where the skin thickens and lichenifies) or scratching (where the skin becomes red with linear erosions, called excoriations, caused by fingernails).

The initial trigger for lichen simplex chronicus often is an infection—often yeast—but overwashing, stress, sweat, heat, urine, irritating lubricants, and use of panty liners also may precipitate the itching. At the office visit, the original infection or other cause of irritation often is no longer present, and only lichen simplex chronicus can be identified.

How to treat lichen simplex chronicus
Management of lichen simplex chronicus requires very sparing application of an ultra-potent topical corticosteroid (clobetasol, halobetasol, or betamethasone dipropionate in an augmented vehicle ointment) twice daily, with the ointment covered with petroleum jelly. Care also must be taken to avoid irritants.

In addition, nighttime sedation helps to interrupt the itch-scratch cycle by preventing rubbing during sleep.

When the skin appears normal and itching has resolved, taper the medication down or off, warning the patient that recurrence is common with any future irritation.

Restart therapy immediately upon recurrence to prevent lichenification and chronic problems.

Second-line medications include calcineurin inhibitors (tacrolimus or pimecrolimus). Although these agents do not contribute to atrophy, they are less effective than topical corticosteroids,⁹ cost more, and can cause burning upon application.

Unlike lichen sclerosus, lichen simplex chronicus does not always recur upon cessation of treatment, and there is no need for concern about an increased risk of malignancy or significant scarring.

Related article: New treatment option for vulvar and vaginal atrophy  Andrew M. Kaunitz, MD (News for your Practice; May 2013)

CASE 4. ORAL AND VULVAR INVOLVEMENT
A 73-year-old patient seeks your help in alleviating longstanding introital itching and rawness, with dyspareunia. She has tried topical estradiol cream intravaginally three times weekly in combination with weekly fluconazole, to no avail.

Physical examination reveals deep red patches and erosions of the vestibule, with complete resorption of the labia minora (FIGURE 4). Patchy redness of the vagina is apparent as well, so you examine the patient’s mouth and find deep redness of the gingivae and erosions of the buccal mucosae, with surrounding white, lacy papules. A wet mount shows a marked increase in lymphocytes and parabasal cells, with a pH of more than 7.

Diagnosis: After correlating the vulvar and oral findings, you make a diagnosis of lichen planus.

Treatment: You initiate halobetasol ointment twice daily, to be applied to the vulva. You also continue vaginal estradiol cream but add hydrocortisone acetate 200 mg compounded vaginal suppositories nightly, as well as clobetasol gel to be applied to oral lesions three times a day. You follow the patient closely for secondary yeast of the mouth and vagina.

Erosive multimucosal lichen planus is a disease of cell-mediated immunity that overwhelmingly affects menopausal women. The most common surfaces involved are the mouth, vagina, rectal mucosa, and vulva; usually, at least two surfaces are affected. The esophagus, extra-auditory canals, nasal mucosa, and eyes also can be involved. Dry, extragenital skin usually is not affected in the setting of erosive vulvovaginal lichen planus.

Vulvar lichen planus most often is controlled with ultra-potent topical corticosteroids (again, clobetasol, halobetasol, or betamethasone dipropionate in an augmented vehicle), but other mucosal surfaces often are more difficult to manage. Although there is no definitive cure for this condition, careful local care, estrogen replacement, and suppression of oral and vulvovaginal candidiasis usually provide relief.

Calcineurin inhibitors (tacrolimus, pimecrolimus) sometimes are useful in patients who improve only partially after treatment with a topical corticosteroid, provided burning with application is tolerable.¹⁰ Systemic immunosuppressants such as hydroxychloroquine, methotrexate, mycophenolate mofetil, azathioprine, cyclosporine, cyclophosphamide, and tumor necrosis factor (TNF) alpha blockers (etanercept, adalimumab, infliximab), as well as oral retinoids, can be added for more recalcitrant disease.¹¹

How to manage disease that affects the vagina
When the vagina is involved in lichen planus, treatment is important to prevent scarring, as well as rawness and pain from irritant contact dermatitis caused by purulent vaginal secretions. Occasionally, a 25-mg hydrocortisone acetate rectal suppository inserted into the vagina nightly improves vaginal lichen planus, but sometimes more potent suppositories, such as doses of 100 to 200 mg, may be compounded. Dilators should be inserted daily to prevent vaginal synechiae.

Oral involvement requires targeted treatment
The mouth is almost always involved in lichen planus. If a dermatologist is not involved in patient care, a prescription for dexamethasone/nystatin elixir (50:50) (5 mL swish, hold, and spit four times daily) can improve oral symptoms remarkably. Alternatively, clobetasol gel applied to affected areas of the mouth three or four times daily can be helpful. Secondary yeast of the vagina and mouth are common with the use of topical corticosteroids.

Careful clinical follow-up is advised
Like uncontrolled lichen sclerosus, erosive lichen planus of the vulva produces scarring and sometimes eventuates into squamous cell carcinoma. Therefore, careful clinical surveillance is warranted. And therapy must be continued to prevent recurrence of lichen planus (as it must be for lichen sclerosus), scarring, and to decrease the risk of squamous cell carcinoma. And like lichen sclerosus, lichen planus sometimes triggers vulvodynia.

CASE 5. MULTIPLE BOILS IN THE GROIN
A 31-year-old morbidly obese African American woman comes to your office with continually evolving boils in the groin. A culture shows Bacterioides spp, Escherichia coli, and Peptococcus spp. In the past, multiple courses of various antibiotics have provided only modest relief.

Physical examination reveals fluctuant nodules, scars, and draining sinus tracts of the hair-bearing vulva and crural crease (FIGURE 5). The axillae are clear.

Diagnosis: Hidradenitis suppurativa.

Treatment: The patient begins taking minocycline 100 mg twice daily. Because she is a smoker, you refer her to an aggressive primary care provider for smoking cessation and weight loss management.

Three months later, the patient is developing only about two nodules a month, managed by early intralesional injections of triamcinolone acetonide.

Hidradenitis suppurativa is sometimes called inverse acne because the underlying pathogenesis is similar to cystic acne. Follicular plugging with keratin debris occurs, with additional keratin, sebaceous material, and normal skin bacteria trapped below the occlusion and distending the follicle. As the follicle wall stretches, thins, and allows for leakage of keratin debris into surrounding dermis, a brisk foreign-body response ­produces a noninfectious abscess.

Hidradenitis suppurativa affects more than 2% of the population.¹² It appears only in areas of the body that contain apocrine glands and in individuals who have double- or triple-outlet follicles that predispose them to follicular occlusion. Therefore, this disease has a genetic component.

Other risk factors include male sex, African genetic background, obesity, and smoking. The prevalence of metabolic syndrome is significantly higher in individuals with hidradenitis suppurativa than in the general population.¹³

Recommended management
Treatments include:

• chronic antibiotics with nonspecific anti-inflammatory activity (tetracyclines, erythromycin, clindamycin, and trimethoprim-sulfamethoxazole)
• intralesional injection of corticosteroids for early nodules (which often aborts their development)
• TNF alpha blockers (etanercept, adalimumab, infliximab)^14–16
• surgical removal of affected skin—the definitive therapy.

Note, however, that anogenital hidradenitis often is too extensive for surgery to be practical. In patients who have localized hidradenitis, primary excision is an excellent early therapy, provided the patient is advised that recurrence may occur in apocrine-containing nearby skin. Aggressive curettage of the roof of the cysts has been performed by some clinicians with good response.

Don’t overlook adjuvant approaches
Smoking cessation and weight loss often are useful.

Other therapies backed by anecdotal evidence include oral contraceptives or spironolactone for their anti-androgen effect, as well as metformin, a more recently studied agent.

Local care with antibacterial soaps and topical antibiotics may be useful for some women.

MORE CASES TO COME
In Part 2 of this series, which will appear in the June 2014 issue of OBG Management, we will discuss the following cases:

• atrophic vagina and atrophic vaginitis
• contact dermatitis
• vulvar aphthae
• desquamative inflammatory vaginitis
• psoriasis.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article. Send your letter to: [email protected] Please include the city and state in which you practice. 

Our specialty sees contraception as a basic element of women’s preventive care. It helps women determine and space their pregnancies; helps ensure healthier pregnancies; and helps many women with health-care concerns not related to pregnancy to better manage their symptoms and stay healthy.

The drafters of the Affordable Care Act (ACA) recognized the importance of contraception to women’s health when they guaranteed coverage of prescription contraceptives and services, including all methods approved by the US Food and Drug Administration, without deductibles or copays, to millions of women through their private health insurance. This policy was vetted and approved by the Institute of Medicine (IOM) and US Department of Health and Human Services (HHS).

The American Congress of Obstetricians and Gynecologists (ACOG) was central to these discussions. ACOG Executive Vice President and CEO Hal C. Lawrence III, MD, offered our women’s health guidelines and guidance to the IOM, the entity designated by the Secretary of HHS to recommend exactly what coverage and services should fall within the category of women’s preventive care. ACOG’s recommendations were broadly accepted by IOM and HHS and are now required coverage for women across the nation.

Related Article: ACOG to legislators: Partnership, not interference  Lucia DiVenere, MA (April 2013)

So, why the confusion and controversy?

Let’s clear up the confusion first.

We’ve heard that private health plans now are required to cover contraceptives without cost sharing. But it’s a little more complicated than that.

CONTRACEPTIVE MANDATE AFFECTS NEW PLANS ONLY
It’s true that the ACA requires new private plans to cover a broad range of preventive services:

• evidence-based screenings and counseling
• routine immunizations
• childhood preventive services
• preventive services for women.

Did you catch the word “new” in that sentence?

Health plans that existed before March 23, 2010—the date the ACA was signed into law—and that haven’t changed in ways that substantially cut benefits or increase costs for consumers are considered “grandfathered plans” and are not required to abide by these and other requirements in the law.

There are two types of grandfathered plans:

• job-based plans—health insurance plans administered through employers can ­continue to enroll people as long as no significant changes are made to coverage
• individual plans—a grandfathered plan purchased by an individual cannot expand coverage beyond that individual.

Any insurer can cancel a grandfathered plan as long as it provides 90-day notice to the plan’s enrollees and offers other coverage options. Because grandfathered plans are exempt from a number of ACA benefits and protections, these plans are required to disclose their status to their enrollees.

The number of people enrolled in grandfathered plans is steadily decreasing. In 2013, 36% of people covered through their jobs were enrolled in a grandfathered health plan, down from 48% in 2012 and 56% in 2011, according to the Kaiser Family Foundation.¹ Here’s a quick look at the consumer protections that do and do not apply to grandfathered plans.

All health plans must:

• end lifetime limits on coverage
• end arbitrary cancellations of health coverage
• cover adult children up to age 26
• provide a Summary of Benefits and Coverage, a short, easy-to-understand summary of what a plan covers and costs
• spend revenue from premiums on health care, not on administrative costs and bonuses.

Grandfathered plans don’t have to:

• cover preventive care for free, including contraceptives
• guarantee your right to appeal
• protect your choice of doctors and access to emergency care
• be held accountable through Rate Review for excessive premium increases.

Nor do grandfathered individual plans (the kind you buy yourself, not the kind you get from an employer) have to end yearly limits on coverage or cover a preexisting health condition.

Right away, then, we have a situation in which some patients may have 100% coverage for contraceptives while others don’t, especially if their plans were in effect before the ACA became law.

Nonprofits with religious ties are exempted, too
There’s a second segment of your patient population that may not have full contraceptive coverage: those who are covered through employment with a religiously affiliated nonprofit. Initially, in August 2011, only health insurance provided through employment with houses of worship was exempted from the requirement to cover contraceptives. In July 2013, this exemption was expanded to address concerns from other religious affiliates, including universities and hospitals.

This “accommodation,” as it’s known, exempts religiously affiliated nonprofits with religious objections from contracting, arranging, paying for, or referring for contraceptive coverage for their employees. Instead, their insurers are required to provide this coverage free of charge to the employer or employees—an attempt to ensure that all women have the same access to care, regardless of their employment setting. This accommodation is available only to organizations that: 

1. oppose the mandate to provide contraceptive coverage because of religious beliefs
2. are nonprofit
3. hold themselves out as religious organizations AND
4. self-certify that they meet the just-stated requirements of 1–3.

Related article: As the Affordable Care Act comes of age, a look behind the headlines  Lucia DiVenere, MA (January 2014)

The rule for small companies
There’s a third group that doesn’t have to provide contraceptive coverage to employees: for-profit companies with fewer than 50 workers. Under the law, these employers have two options:

• Provide no health care: This option carries no penalty but, rather, is an attempt to help small businesses, now that individuals can buy coverage on the exchanges
• Offer health care: If small businesses choose this option, their coverage must include contraceptive care.

So when your patient approaches your front desk to pay her bill, or picks up her contraceptive prescription at the pharmacy, her bill will vary, depending on the age of her plan, her employer’s religious status, and the size of the business she works for. It’s important that you check her coverage with her policy.

Now, on to the controversy.

FOR-PROFIT COMPANIES ALSO SEEK EXEMPTION
Houses of worship are exempted and religiously affiliated nonprofit organizations are offered an accommodation to avoid direct involvement with the contraceptive coverage mandate. More than 40 religiously affiliated nonprofit corporations are currently challenging the mandate, asserting that the accommodation still burdens their religious rights.

What happens when owners of a for-profit corporation claim a religious right to not offer contraceptive coverage to their employees? That’s the question currently before the US Supreme Court. As of this writing, the Court heard arguments on March 25, 2014, and is likely to hand down its decision in two cases in June. The two corporations involved are Conestoga Wood Specialties and Hobby Lobby Stores.

Under the ACA, for-profit employers do not qualify for religious exemptions or accommodations from the contraceptive coverage mandate. As we saw earlier, the mandate varies in its application to these employers by employer size. All for-profit employers with 50 or more employees must provide coverage, unless their coverage is through a grandfathered plan. Employers with fewer than 50 workers have two options. They’re not penalized if they don’t offer any health-care coverage to their employees—but if they do, that coverage must include contraception.

Both Conestoga and Hobby Lobby are major employers. Conestoga Wood has 950 full-time employees. Hobby Lobby operates 514 stores in 41 states, with more than 13,000 employees.

Lower court rulings have been conflicting
The Supreme Court agreed to review and rule on these cases largely to settle widely ­divergent rulings at lower court levels. As of this writing, more than 40 for-profit businesses have challenged the coverage mandate in federal court. The Conestoga and Hobby Lobby owners, like the owners of other businesses challenging the law, say that because they are religious families—Mennonite and Protestant, respectively—and they run their businesses according to their faiths, their religious views extend to their businesses. They claim that the ACA mandate violates their First Amendment right to protection of free exercise of religion as well as their rights under the 1993 Religious Freedom Restoration Act (RFRA), a law enacted to protect individuals from laws that substantially burden their exercise of religion. They are left, they assert, with a choice of providing objectionable coverage or paying a fine, a substantial burden on their freedom of religion.

The key issue before the Court is whether secular for-profit corporations can avoid complying with the legal mandates of the ACA based on the religious beliefs of their owners. To date, five federal circuit courts have ruled on the RFRA claim. Some have determined that corporations have no religious rights. Others have found the opposite. The Supreme Court will attempt to set the path for lower courts to follow.

The outcome of these cases will have a profound effect on women’s health, and may be felt much more broadly in our health-care system. If a business owner can opt out of one sort of coverage based on his or her religious beliefs, then wouldn’t that rule apply to other areas of health care? Employers might choose not to cover childhood immunizations, blood transfusions, or maternity care for single workers. Allowing employers to pick and choose can be risky business.

ACOG joins an amicus brief
ACOG partnered with a number of other preeminent health-care organizations, including the American Academy of Pediatrics, the American College of Nurse-Midwives, the American Society for Reproductive Medicine, the Society for Maternal-Fetal Medicine, Physicians for Reproductive Health, and the International Association of Forensic Nurses, to prepare an amicus brief to the Court on these cases.

The arguments we and our colleagues put forward centered on two points:

• Employers should not be allowed to interfere in the provider-patient relationship
• Allowing employers to veto coverage based on their own religious beliefs has broad and troubling public health implications.

Contraception is an essential component of women’s health care. The Supreme Court could unravel this important new guarantee or protect it for today’s and future generations.

Acknowledgment
The author thanks and acknowledges Sara Needleman Kline, JD, Deputy General Counsel, ACOG, for her helpful review and comments.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice. We will consider publishing your letter in a future issue. Send your letter to: [email protected] Please include the city and state in which you practice. Stay in touch! Your feedback is important to us!

Our specialty sees contraception as a basic element of women’s preventive care. It helps women determine and space their pregnancies; helps ensure healthier pregnancies; and helps many women with health-care concerns not related to pregnancy to better manage their symptoms and stay healthy.

The drafters of the Affordable Care Act (ACA) recognized the importance of contraception to women’s health when they guaranteed coverage of prescription contraceptives and services, including all methods approved by the US Food and Drug Administration, without deductibles or copays, to millions of women through their private health insurance. This policy was vetted and approved by the Institute of Medicine (IOM) and US Department of Health and Human Services (HHS).

The American Congress of Obstetricians and Gynecologists (ACOG) was central to these discussions. ACOG Executive Vice President and CEO Hal C. Lawrence III, MD, offered our women’s health guidelines and guidance to the IOM, the entity designated by the Secretary of HHS to recommend exactly what coverage and services should fall within the category of women’s preventive care. ACOG’s recommendations were broadly accepted by IOM and HHS and are now required coverage for women across the nation.

Related Article: ACOG to legislators: Partnership, not interference  Lucia DiVenere, MA (April 2013)

So, why the confusion and controversy?

Let’s clear up the confusion first.

We’ve heard that private health plans now are required to cover contraceptives without cost sharing. But it’s a little more complicated than that.

CONTRACEPTIVE MANDATE AFFECTS NEW PLANS ONLY
It’s true that the ACA requires new private plans to cover a broad range of preventive services:

• evidence-based screenings and counseling
• routine immunizations
• childhood preventive services
• preventive services for women.

Did you catch the word “new” in that sentence?

Health plans that existed before March 23, 2010—the date the ACA was signed into law—and that haven’t changed in ways that substantially cut benefits or increase costs for consumers are considered “grandfathered plans” and are not required to abide by these and other requirements in the law.

There are two types of grandfathered plans:

• job-based plans—health insurance plans administered through employers can ­continue to enroll people as long as no significant changes are made to coverage
• individual plans—a grandfathered plan purchased by an individual cannot expand coverage beyond that individual.

Any insurer can cancel a grandfathered plan as long as it provides 90-day notice to the plan’s enrollees and offers other coverage options. Because grandfathered plans are exempt from a number of ACA benefits and protections, these plans are required to disclose their status to their enrollees.

The number of people enrolled in grandfathered plans is steadily decreasing. In 2013, 36% of people covered through their jobs were enrolled in a grandfathered health plan, down from 48% in 2012 and 56% in 2011, according to the Kaiser Family Foundation.¹ Here’s a quick look at the consumer protections that do and do not apply to grandfathered plans.

All health plans must:

• end lifetime limits on coverage
• end arbitrary cancellations of health coverage
• cover adult children up to age 26
• provide a Summary of Benefits and Coverage, a short, easy-to-understand summary of what a plan covers and costs
• spend revenue from premiums on health care, not on administrative costs and bonuses.

Grandfathered plans don’t have to:

• cover preventive care for free, including contraceptives
• guarantee your right to appeal
• protect your choice of doctors and access to emergency care
• be held accountable through Rate Review for excessive premium increases.

Nor do grandfathered individual plans (the kind you buy yourself, not the kind you get from an employer) have to end yearly limits on coverage or cover a preexisting health condition.

Right away, then, we have a situation in which some patients may have 100% coverage for contraceptives while others don’t, especially if their plans were in effect before the ACA became law.

Nonprofits with religious ties are exempted, too
There’s a second segment of your patient population that may not have full contraceptive coverage: those who are covered through employment with a religiously affiliated nonprofit. Initially, in August 2011, only health insurance provided through employment with houses of worship was exempted from the requirement to cover contraceptives. In July 2013, this exemption was expanded to address concerns from other religious affiliates, including universities and hospitals.

This “accommodation,” as it’s known, exempts religiously affiliated nonprofits with religious objections from contracting, arranging, paying for, or referring for contraceptive coverage for their employees. Instead, their insurers are required to provide this coverage free of charge to the employer or employees—an attempt to ensure that all women have the same access to care, regardless of their employment setting. This accommodation is available only to organizations that: 

1. oppose the mandate to provide contraceptive coverage because of religious beliefs
2. are nonprofit
3. hold themselves out as religious organizations AND
4. self-certify that they meet the just-stated requirements of 1–3.

Related article: As the Affordable Care Act comes of age, a look behind the headlines  Lucia DiVenere, MA (January 2014)

The rule for small companies
There’s a third group that doesn’t have to provide contraceptive coverage to employees: for-profit companies with fewer than 50 workers. Under the law, these employers have two options:

• Provide no health care: This option carries no penalty but, rather, is an attempt to help small businesses, now that individuals can buy coverage on the exchanges
• Offer health care: If small businesses choose this option, their coverage must include contraceptive care.

So when your patient approaches your front desk to pay her bill, or picks up her contraceptive prescription at the pharmacy, her bill will vary, depending on the age of her plan, her employer’s religious status, and the size of the business she works for. It’s important that you check her coverage with her policy.

Now, on to the controversy.

FOR-PROFIT COMPANIES ALSO SEEK EXEMPTION
Houses of worship are exempted and religiously affiliated nonprofit organizations are offered an accommodation to avoid direct involvement with the contraceptive coverage mandate. More than 40 religiously affiliated nonprofit corporations are currently challenging the mandate, asserting that the accommodation still burdens their religious rights.

What happens when owners of a for-profit corporation claim a religious right to not offer contraceptive coverage to their employees? That’s the question currently before the US Supreme Court. As of this writing, the Court heard arguments on March 25, 2014, and is likely to hand down its decision in two cases in June. The two corporations involved are Conestoga Wood Specialties and Hobby Lobby Stores.

Under the ACA, for-profit employers do not qualify for religious exemptions or accommodations from the contraceptive coverage mandate. As we saw earlier, the mandate varies in its application to these employers by employer size. All for-profit employers with 50 or more employees must provide coverage, unless their coverage is through a grandfathered plan. Employers with fewer than 50 workers have two options. They’re not penalized if they don’t offer any health-care coverage to their employees—but if they do, that coverage must include contraception.

Both Conestoga and Hobby Lobby are major employers. Conestoga Wood has 950 full-time employees. Hobby Lobby operates 514 stores in 41 states, with more than 13,000 employees.

Lower court rulings have been conflicting
The Supreme Court agreed to review and rule on these cases largely to settle widely ­divergent rulings at lower court levels. As of this writing, more than 40 for-profit businesses have challenged the coverage mandate in federal court. The Conestoga and Hobby Lobby owners, like the owners of other businesses challenging the law, say that because they are religious families—Mennonite and Protestant, respectively—and they run their businesses according to their faiths, their religious views extend to their businesses. They claim that the ACA mandate violates their First Amendment right to protection of free exercise of religion as well as their rights under the 1993 Religious Freedom Restoration Act (RFRA), a law enacted to protect individuals from laws that substantially burden their exercise of religion. They are left, they assert, with a choice of providing objectionable coverage or paying a fine, a substantial burden on their freedom of religion.

The key issue before the Court is whether secular for-profit corporations can avoid complying with the legal mandates of the ACA based on the religious beliefs of their owners. To date, five federal circuit courts have ruled on the RFRA claim. Some have determined that corporations have no religious rights. Others have found the opposite. The Supreme Court will attempt to set the path for lower courts to follow.

The outcome of these cases will have a profound effect on women’s health, and may be felt much more broadly in our health-care system. If a business owner can opt out of one sort of coverage based on his or her religious beliefs, then wouldn’t that rule apply to other areas of health care? Employers might choose not to cover childhood immunizations, blood transfusions, or maternity care for single workers. Allowing employers to pick and choose can be risky business.

ACOG joins an amicus brief
ACOG partnered with a number of other preeminent health-care organizations, including the American Academy of Pediatrics, the American College of Nurse-Midwives, the American Society for Reproductive Medicine, the Society for Maternal-Fetal Medicine, Physicians for Reproductive Health, and the International Association of Forensic Nurses, to prepare an amicus brief to the Court on these cases.

The arguments we and our colleagues put forward centered on two points:

• Employers should not be allowed to interfere in the provider-patient relationship
• Allowing employers to veto coverage based on their own religious beliefs has broad and troubling public health implications.

Contraception is an essential component of women’s health care. The Supreme Court could unravel this important new guarantee or protect it for today’s and future generations.

Acknowledgment
The author thanks and acknowledges Sara Needleman Kline, JD, Deputy General Counsel, ACOG, for her helpful review and comments.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice. We will consider publishing your letter in a future issue. Send your letter to: [email protected] Please include the city and state in which you practice. Stay in touch! Your feedback is important to us!

Our specialty sees contraception as a basic element of women’s preventive care. It helps women determine and space their pregnancies; helps ensure healthier pregnancies; and helps many women with health-care concerns not related to pregnancy to better manage their symptoms and stay healthy.

The drafters of the Affordable Care Act (ACA) recognized the importance of contraception to women’s health when they guaranteed coverage of prescription contraceptives and services, including all methods approved by the US Food and Drug Administration, without deductibles or copays, to millions of women through their private health insurance. This policy was vetted and approved by the Institute of Medicine (IOM) and US Department of Health and Human Services (HHS).

The American Congress of Obstetricians and Gynecologists (ACOG) was central to these discussions. ACOG Executive Vice President and CEO Hal C. Lawrence III, MD, offered our women’s health guidelines and guidance to the IOM, the entity designated by the Secretary of HHS to recommend exactly what coverage and services should fall within the category of women’s preventive care. ACOG’s recommendations were broadly accepted by IOM and HHS and are now required coverage for women across the nation.

Related Article: ACOG to legislators: Partnership, not interference  Lucia DiVenere, MA (April 2013)

So, why the confusion and controversy?

Let’s clear up the confusion first.

We’ve heard that private health plans now are required to cover contraceptives without cost sharing. But it’s a little more complicated than that.

CONTRACEPTIVE MANDATE AFFECTS NEW PLANS ONLY
It’s true that the ACA requires new private plans to cover a broad range of preventive services:

• evidence-based screenings and counseling
• routine immunizations
• childhood preventive services
• preventive services for women.

Did you catch the word “new” in that sentence?

Health plans that existed before March 23, 2010—the date the ACA was signed into law—and that haven’t changed in ways that substantially cut benefits or increase costs for consumers are considered “grandfathered plans” and are not required to abide by these and other requirements in the law.

There are two types of grandfathered plans:

• job-based plans—health insurance plans administered through employers can ­continue to enroll people as long as no significant changes are made to coverage
• individual plans—a grandfathered plan purchased by an individual cannot expand coverage beyond that individual.

Any insurer can cancel a grandfathered plan as long as it provides 90-day notice to the plan’s enrollees and offers other coverage options. Because grandfathered plans are exempt from a number of ACA benefits and protections, these plans are required to disclose their status to their enrollees.

The number of people enrolled in grandfathered plans is steadily decreasing. In 2013, 36% of people covered through their jobs were enrolled in a grandfathered health plan, down from 48% in 2012 and 56% in 2011, according to the Kaiser Family Foundation.¹ Here’s a quick look at the consumer protections that do and do not apply to grandfathered plans.

All health plans must:

• end lifetime limits on coverage
• end arbitrary cancellations of health coverage
• cover adult children up to age 26
• provide a Summary of Benefits and Coverage, a short, easy-to-understand summary of what a plan covers and costs
• spend revenue from premiums on health care, not on administrative costs and bonuses.

Grandfathered plans don’t have to:

• cover preventive care for free, including contraceptives
• guarantee your right to appeal
• protect your choice of doctors and access to emergency care
• be held accountable through Rate Review for excessive premium increases.

Nor do grandfathered individual plans (the kind you buy yourself, not the kind you get from an employer) have to end yearly limits on coverage or cover a preexisting health condition.

Right away, then, we have a situation in which some patients may have 100% coverage for contraceptives while others don’t, especially if their plans were in effect before the ACA became law.

Nonprofits with religious ties are exempted, too
There’s a second segment of your patient population that may not have full contraceptive coverage: those who are covered through employment with a religiously affiliated nonprofit. Initially, in August 2011, only health insurance provided through employment with houses of worship was exempted from the requirement to cover contraceptives. In July 2013, this exemption was expanded to address concerns from other religious affiliates, including universities and hospitals.

This “accommodation,” as it’s known, exempts religiously affiliated nonprofits with religious objections from contracting, arranging, paying for, or referring for contraceptive coverage for their employees. Instead, their insurers are required to provide this coverage free of charge to the employer or employees—an attempt to ensure that all women have the same access to care, regardless of their employment setting. This accommodation is available only to organizations that: 

1. oppose the mandate to provide contraceptive coverage because of religious beliefs
2. are nonprofit
3. hold themselves out as religious organizations AND
4. self-certify that they meet the just-stated requirements of 1–3.

Related article: As the Affordable Care Act comes of age, a look behind the headlines  Lucia DiVenere, MA (January 2014)

The rule for small companies
There’s a third group that doesn’t have to provide contraceptive coverage to employees: for-profit companies with fewer than 50 workers. Under the law, these employers have two options:

• Provide no health care: This option carries no penalty but, rather, is an attempt to help small businesses, now that individuals can buy coverage on the exchanges
• Offer health care: If small businesses choose this option, their coverage must include contraceptive care.

So when your patient approaches your front desk to pay her bill, or picks up her contraceptive prescription at the pharmacy, her bill will vary, depending on the age of her plan, her employer’s religious status, and the size of the business she works for. It’s important that you check her coverage with her policy.

Now, on to the controversy.

FOR-PROFIT COMPANIES ALSO SEEK EXEMPTION
Houses of worship are exempted and religiously affiliated nonprofit organizations are offered an accommodation to avoid direct involvement with the contraceptive coverage mandate. More than 40 religiously affiliated nonprofit corporations are currently challenging the mandate, asserting that the accommodation still burdens their religious rights.

What happens when owners of a for-profit corporation claim a religious right to not offer contraceptive coverage to their employees? That’s the question currently before the US Supreme Court. As of this writing, the Court heard arguments on March 25, 2014, and is likely to hand down its decision in two cases in June. The two corporations involved are Conestoga Wood Specialties and Hobby Lobby Stores.

Under the ACA, for-profit employers do not qualify for religious exemptions or accommodations from the contraceptive coverage mandate. As we saw earlier, the mandate varies in its application to these employers by employer size. All for-profit employers with 50 or more employees must provide coverage, unless their coverage is through a grandfathered plan. Employers with fewer than 50 workers have two options. They’re not penalized if they don’t offer any health-care coverage to their employees—but if they do, that coverage must include contraception.

Both Conestoga and Hobby Lobby are major employers. Conestoga Wood has 950 full-time employees. Hobby Lobby operates 514 stores in 41 states, with more than 13,000 employees.

Lower court rulings have been conflicting
The Supreme Court agreed to review and rule on these cases largely to settle widely ­divergent rulings at lower court levels. As of this writing, more than 40 for-profit businesses have challenged the coverage mandate in federal court. The Conestoga and Hobby Lobby owners, like the owners of other businesses challenging the law, say that because they are religious families—Mennonite and Protestant, respectively—and they run their businesses according to their faiths, their religious views extend to their businesses. They claim that the ACA mandate violates their First Amendment right to protection of free exercise of religion as well as their rights under the 1993 Religious Freedom Restoration Act (RFRA), a law enacted to protect individuals from laws that substantially burden their exercise of religion. They are left, they assert, with a choice of providing objectionable coverage or paying a fine, a substantial burden on their freedom of religion.

The key issue before the Court is whether secular for-profit corporations can avoid complying with the legal mandates of the ACA based on the religious beliefs of their owners. To date, five federal circuit courts have ruled on the RFRA claim. Some have determined that corporations have no religious rights. Others have found the opposite. The Supreme Court will attempt to set the path for lower courts to follow.

The outcome of these cases will have a profound effect on women’s health, and may be felt much more broadly in our health-care system. If a business owner can opt out of one sort of coverage based on his or her religious beliefs, then wouldn’t that rule apply to other areas of health care? Employers might choose not to cover childhood immunizations, blood transfusions, or maternity care for single workers. Allowing employers to pick and choose can be risky business.

ACOG joins an amicus brief
ACOG partnered with a number of other preeminent health-care organizations, including the American Academy of Pediatrics, the American College of Nurse-Midwives, the American Society for Reproductive Medicine, the Society for Maternal-Fetal Medicine, Physicians for Reproductive Health, and the International Association of Forensic Nurses, to prepare an amicus brief to the Court on these cases.

The arguments we and our colleagues put forward centered on two points:

• Employers should not be allowed to interfere in the provider-patient relationship
• Allowing employers to veto coverage based on their own religious beliefs has broad and troubling public health implications.

Contraception is an essential component of women’s health care. The Supreme Court could unravel this important new guarantee or protect it for today’s and future generations.

Acknowledgment
The author thanks and acknowledges Sara Needleman Kline, JD, Deputy General Counsel, ACOG, for her helpful review and comments.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice. We will consider publishing your letter in a future issue. Send your letter to: [email protected] Please include the city and state in which you practice. Stay in touch! Your feedback is important to us!

Endometrial cancer is the most common gynecologic cancer in the developed world, and its incidence is rising—increasing 50% in the past 10 years in Norway alone. Because endometrial hyperplasia is a precursor to cancer, it is vital that we ensure effective treatment for this prevalent problem. Hysterectomy is one option—used most commonly for complex atypical hyperplasia—but oral progestins have become the norm in women who desire to preserve their uterus when surgery is not the best option.

In this randomized trial from Norway, Orbo and colleagues randomly assigned 170 women aged 30 to 70 years to one of three treatment groups:

• placement of an LNG-IUS (Mirena)
• medroxyprogesterone acetate (MPA) 10 mg for 10 days per cycle
• continuous MPA 10 mg.

All women in the trial had low- or medium-risk endometrial hyperplasia.

After 6 months, women in the LNG-IUS arm had a 100% response rate, compared with 96% for the continuous MPA group and 69% for cyclic MPA.

Related article: When should a menopausal woman discontinue hormone therapy? Andrew M. Kaunitz, MD (Cases in Menopause; March 2014)

Histologic interpretation of hyperplasia is highly subjective
There are several problems inherent in a study like this. Although Orbo and colleagues address these problems tangentially, the problems affect the interpretation of results.

For example, the histologic interpretation of endometrial hyperplasia is known to be associated with low interobserver agreement.¹ Clinical trials that use endometrial safety as an outcome require two primary pathologists to review the histology, with a third pathologist standing by in case of disagreement.

In the current study, two pathologists in the same department independently reviewed the histology. Orbo and colleagues used World Health Organization criteria for hyperplasia. However, as an adjunct, they also used a D-evaluation morphometric assessment.² When I put in a casual call to local gynecologic pathologists, they told me that neither the D-classification nor the immunochemical-detected PTEN protein is used in routine clinical practice to determine the risk of progression.³

Intermittent use of oral MPA is known to be ineffective
The cyclic use of MPA for only 10 days overlooks epidemiology from estrogen-progestin replacement regimens in postmenopausal women. Use of a progestin for fewer than 12 days during estrogen replacement increases the risk of endometrial cancer.⁴ Exogenous progestin must be given for more than 12 days to inhibit hyperplasia and neoplasia. The dose itself is not critical; the duration of administration is.

In the current study, both the LNG-IUS and continuous MPA met this criterion. Local delivery of the progestin with the LNG-IUS allows for a reduction of the delivered dose and mitigates side effects even as it uses a more potent progestin than MPA.^5–8

Assessment of outcomes was questionable
Although Orbo and colleagues suggest that there is no evidence of progression with the LNG-IUS and continuous MPA, they relied on a Pipelle biopsy of the endometrium performed after 6 months of treatment. The clinical settings that led to the hyperplasia in the first place are poorly characterized as either pre- or postmenopausal, and the cause of the hyperplasia is not identified. This approach overlooks such realities as the increased incidence of simple hyperplasia in many perimenopausal women, which appears to regress with further reduction in ovarian estrogen.⁹

The final outcomes for women in the cyclic MPA arm are not provided. Hyperplasia without atypia progresses to carcinoma in 1.6% of cases, but when atypia is present, the progression rate is 23%.¹

What this evidence means for practice
In low-risk women with simple hyperplasia, the use of targeted low-dose progestins—oral or intrauterine—is appealing. While Orbo and colleagues present an interesting study, they do not definitively establish the optimal intervention.
As we enter a cost-conscious phase of medicine in the United States, we may discover that oral generic MPA (given continuously) may be the most cost-effective treatment despite the option of delivering a low-dose progestin via intrauterine device.
David F. Archer, MD

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice. We will consider publishing your letter in a future issue. Send your letter to: [email protected] Please include the city and state in which you practice. Stay in touch! Your feedback is important to us!

Endometrial cancer is the most common gynecologic cancer in the developed world, and its incidence is rising—increasing 50% in the past 10 years in Norway alone. Because endometrial hyperplasia is a precursor to cancer, it is vital that we ensure effective treatment for this prevalent problem. Hysterectomy is one option—used most commonly for complex atypical hyperplasia—but oral progestins have become the norm in women who desire to preserve their uterus when surgery is not the best option.

In this randomized trial from Norway, Orbo and colleagues randomly assigned 170 women aged 30 to 70 years to one of three treatment groups:

• placement of an LNG-IUS (Mirena)
• medroxyprogesterone acetate (MPA) 10 mg for 10 days per cycle
• continuous MPA 10 mg.

All women in the trial had low- or medium-risk endometrial hyperplasia.

After 6 months, women in the LNG-IUS arm had a 100% response rate, compared with 96% for the continuous MPA group and 69% for cyclic MPA.

Related article: When should a menopausal woman discontinue hormone therapy? Andrew M. Kaunitz, MD (Cases in Menopause; March 2014)

Histologic interpretation of hyperplasia is highly subjective
There are several problems inherent in a study like this. Although Orbo and colleagues address these problems tangentially, the problems affect the interpretation of results.

For example, the histologic interpretation of endometrial hyperplasia is known to be associated with low interobserver agreement.¹ Clinical trials that use endometrial safety as an outcome require two primary pathologists to review the histology, with a third pathologist standing by in case of disagreement.

In the current study, two pathologists in the same department independently reviewed the histology. Orbo and colleagues used World Health Organization criteria for hyperplasia. However, as an adjunct, they also used a D-evaluation morphometric assessment.² When I put in a casual call to local gynecologic pathologists, they told me that neither the D-classification nor the immunochemical-detected PTEN protein is used in routine clinical practice to determine the risk of progression.³

Intermittent use of oral MPA is known to be ineffective
The cyclic use of MPA for only 10 days overlooks epidemiology from estrogen-progestin replacement regimens in postmenopausal women. Use of a progestin for fewer than 12 days during estrogen replacement increases the risk of endometrial cancer.⁴ Exogenous progestin must be given for more than 12 days to inhibit hyperplasia and neoplasia. The dose itself is not critical; the duration of administration is.

In the current study, both the LNG-IUS and continuous MPA met this criterion. Local delivery of the progestin with the LNG-IUS allows for a reduction of the delivered dose and mitigates side effects even as it uses a more potent progestin than MPA.^5–8

Assessment of outcomes was questionable
Although Orbo and colleagues suggest that there is no evidence of progression with the LNG-IUS and continuous MPA, they relied on a Pipelle biopsy of the endometrium performed after 6 months of treatment. The clinical settings that led to the hyperplasia in the first place are poorly characterized as either pre- or postmenopausal, and the cause of the hyperplasia is not identified. This approach overlooks such realities as the increased incidence of simple hyperplasia in many perimenopausal women, which appears to regress with further reduction in ovarian estrogen.⁹

The final outcomes for women in the cyclic MPA arm are not provided. Hyperplasia without atypia progresses to carcinoma in 1.6% of cases, but when atypia is present, the progression rate is 23%.¹

What this evidence means for practice
In low-risk women with simple hyperplasia, the use of targeted low-dose progestins—oral or intrauterine—is appealing. While Orbo and colleagues present an interesting study, they do not definitively establish the optimal intervention.
As we enter a cost-conscious phase of medicine in the United States, we may discover that oral generic MPA (given continuously) may be the most cost-effective treatment despite the option of delivering a low-dose progestin via intrauterine device.
David F. Archer, MD

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice. We will consider publishing your letter in a future issue. Send your letter to: [email protected] Please include the city and state in which you practice. Stay in touch! Your feedback is important to us!

Endometrial cancer is the most common gynecologic cancer in the developed world, and its incidence is rising—increasing 50% in the past 10 years in Norway alone. Because endometrial hyperplasia is a precursor to cancer, it is vital that we ensure effective treatment for this prevalent problem. Hysterectomy is one option—used most commonly for complex atypical hyperplasia—but oral progestins have become the norm in women who desire to preserve their uterus when surgery is not the best option.

In this randomized trial from Norway, Orbo and colleagues randomly assigned 170 women aged 30 to 70 years to one of three treatment groups:

• placement of an LNG-IUS (Mirena)
• medroxyprogesterone acetate (MPA) 10 mg for 10 days per cycle
• continuous MPA 10 mg.

All women in the trial had low- or medium-risk endometrial hyperplasia.

After 6 months, women in the LNG-IUS arm had a 100% response rate, compared with 96% for the continuous MPA group and 69% for cyclic MPA.

Related article: When should a menopausal woman discontinue hormone therapy? Andrew M. Kaunitz, MD (Cases in Menopause; March 2014)

Histologic interpretation of hyperplasia is highly subjective
There are several problems inherent in a study like this. Although Orbo and colleagues address these problems tangentially, the problems affect the interpretation of results.

For example, the histologic interpretation of endometrial hyperplasia is known to be associated with low interobserver agreement.¹ Clinical trials that use endometrial safety as an outcome require two primary pathologists to review the histology, with a third pathologist standing by in case of disagreement.

In the current study, two pathologists in the same department independently reviewed the histology. Orbo and colleagues used World Health Organization criteria for hyperplasia. However, as an adjunct, they also used a D-evaluation morphometric assessment.² When I put in a casual call to local gynecologic pathologists, they told me that neither the D-classification nor the immunochemical-detected PTEN protein is used in routine clinical practice to determine the risk of progression.³

Intermittent use of oral MPA is known to be ineffective
The cyclic use of MPA for only 10 days overlooks epidemiology from estrogen-progestin replacement regimens in postmenopausal women. Use of a progestin for fewer than 12 days during estrogen replacement increases the risk of endometrial cancer.⁴ Exogenous progestin must be given for more than 12 days to inhibit hyperplasia and neoplasia. The dose itself is not critical; the duration of administration is.

In the current study, both the LNG-IUS and continuous MPA met this criterion. Local delivery of the progestin with the LNG-IUS allows for a reduction of the delivered dose and mitigates side effects even as it uses a more potent progestin than MPA.^5–8

Assessment of outcomes was questionable
Although Orbo and colleagues suggest that there is no evidence of progression with the LNG-IUS and continuous MPA, they relied on a Pipelle biopsy of the endometrium performed after 6 months of treatment. The clinical settings that led to the hyperplasia in the first place are poorly characterized as either pre- or postmenopausal, and the cause of the hyperplasia is not identified. This approach overlooks such realities as the increased incidence of simple hyperplasia in many perimenopausal women, which appears to regress with further reduction in ovarian estrogen.⁹

The final outcomes for women in the cyclic MPA arm are not provided. Hyperplasia without atypia progresses to carcinoma in 1.6% of cases, but when atypia is present, the progression rate is 23%.¹

What this evidence means for practice
In low-risk women with simple hyperplasia, the use of targeted low-dose progestins—oral or intrauterine—is appealing. While Orbo and colleagues present an interesting study, they do not definitively establish the optimal intervention.
As we enter a cost-conscious phase of medicine in the United States, we may discover that oral generic MPA (given continuously) may be the most cost-effective treatment despite the option of delivering a low-dose progestin via intrauterine device.
David F. Archer, MD

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice. We will consider publishing your letter in a future issue. Send your letter to: [email protected] Please include the city and state in which you practice. Stay in touch! Your feedback is important to us!

The introduction of amniocentesis in the 1960s brought to prenatal diagnosticians the ability to detect fetal chromosome abnormalities and certain structural defects (including neural tube defects). Since that time, a goal for these practitioners has been the development of effective screening algorithms to better identify women at high risk for detectable fetal abnormalities in concert with the advent of safer and more accessible diagnostic tests, with the eventual aim being the development of a noninvasive prenatal diagnostic test.

Postamniocentesis advancements have included the identification of maternal serum analytes as well as the incorporation of first-trimester ultrasonographic measurements of the fetal nuchal translucency (NT) and nasal bone, all associated with an improved ability to identify women at increased risk for fetal trisomies 21 and 18 as well as some other fetal abnormalities. In addition, targeted ultrasound has greatly improved the ability to detect fetal structural and growth abnormalities in women of all risk levels, although it remains a highly subjective process with considerable inter/intraoperator and equipment variability.

Related article: NIPT is expanding rapidly--but don't throw out that CVS kit just yet! (Update on Obstetrics; Jaimey M. Pauli, MD, and John T. Repke, MD; January 2014)

Noninvasive prenatal screening has the advantages of being noninvasive and carrying no increased risk for fetal loss compared with chorionic villus sampling (CVS) and amniocentesis, which are associated with a small increased risk for pregnancy loss (1/500 to 1/1,500 over baseline risk for loss). However, noninvasive screening is limited compared with diagnostic procedures because it provides only a risk adjustment rather than a definitive diagnostic outcome and is mostly limited to assessment for fetal trisomies 18 and 21.

Targeted ultrasound can identify structural abnormalities associated with other chromosomal, genetic, and genomic abnormalities, but again depends on operator experience, equipment used, maternal habitus, and fetal position. Accordingly, considerable interest has remained in developing a more effective approach for detecting fetal aneuploidy and other fetal abnormalities, including assays that eventually could serve to provide noninvasive prenatal diagnosis.

RECENT ADVANCES BRING US CLOSER TO OUR ULTIMATE GOAL
The recent introduction of circulating cell-free nucleic acids (ccfna) technologies for prenatal screening for common fetal aneuploidies, better known as noninvasive prenatal testing, or NIPT, has presented a far more effective prenatal screening protocol for certain groups of women compared with the aforementioned screening algorithms that rely on measurements of the fetal NT in the late first trimester and maternal serum measurements of analytes in the first and second trimesters.

Currently, four NIPT screening products are available commercially in the United States: MaterniT21 Plus (Sequenom, San Diego, California); Verifi (Illumina, San Diego, California); Harmony Prenatal Test (Ariosa Diagnostics, San Jose, California); and Panorama Prenatal Test (Natera, San Carlos, California). While the technologies and algorithms used by each of the companies differ, they all rely on the premise that 5% to 10% of ccfna in maternal blood are fetal in nature.¹ Calculating the ratios of the expected amount of each chromosome-specific nucleic acid to that actually measured in the sample, a prediction of a normal or abnormal complement for that specific chromosome is then made. None of the commercially available tests specifically identify fetal DNA or differentiate fetal from maternal DNA.

Current validation studies have thus far limited the offering of NIPT to women at increased risk for fetal aneuploidy, including those:^2–6

• of advanced maternal age
• with a positive conventional screening test
• with abnormal ultrasound results suggestive of aneuploidy, or
• who have had a prior pregnancy with a chromosome aneuploidy found in the NIPT panel.

Studies of all available technologies tested on women at increased risk for fetal aneuploidy have thus far shown considerably higher sensitivities and specificities and detection rates for fetal trisomies 21, 18, and 13 than conventional screening algorithms, although detection rates for trisomy 13 are slightly lower than those observed for trisomies 21 and 18.

WE STILL HAVE MANY HURDLES TO LEAP
However, the groups of women at high risk for fetal aneuploidy just outlined represent only a small segment of the community of pregnant women. A multicenter study involving 1,914 women published February 2014 in the New England Journal of Medicine⁷ showed considerably and significantly lower false-positive rates and higher positive predictive values for the detection of trisomies 21 and 18 by NIPT compared with conventional fetal aneuploidy screening. This study incorporated women at low risk for fetal aneuploidies in the study cohort, although women at high risk (based on the stated range of maternal age) also were included in the cohort. Unfortunately, no information was provided in the report about the percentage of low-risk women among the study participants.

Related articles:
Noninvasive prenatal DNA testing: Who is using it, and how? Audiocast, June 2013
Noninvasive prenatal DNA tests are unproven and costly  David A. Carpenter, MD (Comment & Controversy; September 2013)

Another concern about the published accuracy of NIPT clinical assays was recently sounded by Menutti and colleagues.⁸ The authors cited recent cases of positive NIPT outcomes for fetal trisomies 18 and 13 that were not confirmed by diagnostic testing of the pregnancies in question. The authors pondered whether such cases may reflect a limitation of the positive predictive values attributed to NIPT assays and that such limitations may carry profound inaccuracies in determining the accuracy of such protocols for rare aneuploidies.

While the improved detection rates for NIPT compared with conventional screening are not surprising, guidelines published by the American College of Obstetricians and Gynecologists still do not recommend the use of NIPT for the screening of low-risk women because of insufficient evaluation of ccfna technologies in the screening of such pregnancies.³ This also applies to twin pregnancies, despite preliminary studies showing comparable detection of trisomies 18 and 21 in such pregnancies compared with singleton pregnancies.^3,9

There are no direct comparative studies of the four commercially available screening products, thus precluding a robust comparison and determination of the best existing method to use.

SO, WHERE ARE WE WITH NIPT EXACTLY?
The recent introduction of NIPT into routine obstetric care has left many clinicians with a wide range of questions, many of which cannot be answered because of little or no information, robust or otherwise, to formulate an accurate and cogent response. So let’s state what we know based on the available evidence, recognizing that this will likely change, perhaps considerably, in the weeks and months ahead.

NIPT is a far superior approach, compared with conventional screening approaches, to screening for fetal trisomies 21, 18, and 13 in women carrying singleton pregnancies who are at an increased risk for fetal chromosome abnormalities.

In our current understanding of prenatal screening and diagnosis, NIPT does not provide either the comprehensive approach or the diagnostic accuracy associated with CVS and amniocentesis. As such, NIPT is not a suitable replacement for prenatal diagnostic procedures.

However, its application to screening a low-risk population for the common fetal aneuploidies, as well as in twin pregnancies, has been supported by initial studies, and the inclusion of other clinical outcomes—including other chromosome abnormalities, such as X and Y aneuploidies, trisomy 16, and triploidy^10,11 and certain genomic abnormalities (eg, 22q deletions)—in the screening algorithm will expand the future clinical applications of NIPT screening.

DOES NIPT CHANGE OUR CONCEPTS OF SCREENING AND DIAGNOSIS?
This question is simple but profound and is perhaps the most important to be asked and addressed. Is a screening algorithm that has a similar sensitivity and specificity to that of CVS and amniocentesis for the most common fetal trisomies in the first and second trimesters sufficient to replace invasive testing for most women? Does the ability to detect fetal genomic abnormalities with microarray analyses of fetal cells obtained by CVS or amniocentesis provide a far greater benefit than that possible with any screening algorithm?

With renewed interest in the cost of health-care screening and diagnosis, we need to consider how comprehensive and accurate our prenatal screening and diagnostic tests should be and whether such improvements are desired or even possible from a clinical or economic viewpoint. In addition, the development of new technologies, such as the capture and analysis of fetal cells in maternal blood, presents the potential for a direct diagnostic fetal assay without the risks of an invasive procedure.

BIAS-FREE COUNSELING CANNOT BE OVERLOOKED
That being said, the current role of NIPT and other screening protocols in obstetric care needs to be clearly communicated to women who are considering their fetal assessment options, with emphasis placed on the capabilities and limitations of prenatal screening (even the newer ccfna-based options), the actual risks associated with invasive testing, and the ability of invasive testing to provide expanded fetal information with the use of microarray analyses.

As it has been from the beginning of prenatal testing in the 1960s, counseling continues to be the most important part of the prenatal screening and diagnostic process and it is needed to facilitate clinical decisions made by women and couples. Counseling must include an accurate communication of the risks, benefits, and limitations of the aforementioned options and issues, and should be provided in a manner that strives to be free of bias, direction, and the personal opinions of the counselor.

In order to provide such counseling, we must remain informed of the ongoing work in the field of prenatal testing, a task that has become more challenging with the rapid release of a considerable amount of new information on prenatal screening technologies over the past 2 years. This will likely continue, and perhaps become even more frenetic, with the expected release of additional information on the clinical applications of ccfna technologies in the near future as well as the development of new technologies applicable for the screening and diagnosis of fetal abnormalities.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article. Send your letter to: [email protected] Please include the city and state in which you practice.

The introduction of amniocentesis in the 1960s brought to prenatal diagnosticians the ability to detect fetal chromosome abnormalities and certain structural defects (including neural tube defects). Since that time, a goal for these practitioners has been the development of effective screening algorithms to better identify women at high risk for detectable fetal abnormalities in concert with the advent of safer and more accessible diagnostic tests, with the eventual aim being the development of a noninvasive prenatal diagnostic test.

Postamniocentesis advancements have included the identification of maternal serum analytes as well as the incorporation of first-trimester ultrasonographic measurements of the fetal nuchal translucency (NT) and nasal bone, all associated with an improved ability to identify women at increased risk for fetal trisomies 21 and 18 as well as some other fetal abnormalities. In addition, targeted ultrasound has greatly improved the ability to detect fetal structural and growth abnormalities in women of all risk levels, although it remains a highly subjective process with considerable inter/intraoperator and equipment variability.

Related article: NIPT is expanding rapidly--but don't throw out that CVS kit just yet! (Update on Obstetrics; Jaimey M. Pauli, MD, and John T. Repke, MD; January 2014)

Noninvasive prenatal screening has the advantages of being noninvasive and carrying no increased risk for fetal loss compared with chorionic villus sampling (CVS) and amniocentesis, which are associated with a small increased risk for pregnancy loss (1/500 to 1/1,500 over baseline risk for loss). However, noninvasive screening is limited compared with diagnostic procedures because it provides only a risk adjustment rather than a definitive diagnostic outcome and is mostly limited to assessment for fetal trisomies 18 and 21.

Targeted ultrasound can identify structural abnormalities associated with other chromosomal, genetic, and genomic abnormalities, but again depends on operator experience, equipment used, maternal habitus, and fetal position. Accordingly, considerable interest has remained in developing a more effective approach for detecting fetal aneuploidy and other fetal abnormalities, including assays that eventually could serve to provide noninvasive prenatal diagnosis.

RECENT ADVANCES BRING US CLOSER TO OUR ULTIMATE GOAL
The recent introduction of circulating cell-free nucleic acids (ccfna) technologies for prenatal screening for common fetal aneuploidies, better known as noninvasive prenatal testing, or NIPT, has presented a far more effective prenatal screening protocol for certain groups of women compared with the aforementioned screening algorithms that rely on measurements of the fetal NT in the late first trimester and maternal serum measurements of analytes in the first and second trimesters.

Currently, four NIPT screening products are available commercially in the United States: MaterniT21 Plus (Sequenom, San Diego, California); Verifi (Illumina, San Diego, California); Harmony Prenatal Test (Ariosa Diagnostics, San Jose, California); and Panorama Prenatal Test (Natera, San Carlos, California). While the technologies and algorithms used by each of the companies differ, they all rely on the premise that 5% to 10% of ccfna in maternal blood are fetal in nature.¹ Calculating the ratios of the expected amount of each chromosome-specific nucleic acid to that actually measured in the sample, a prediction of a normal or abnormal complement for that specific chromosome is then made. None of the commercially available tests specifically identify fetal DNA or differentiate fetal from maternal DNA.

Current validation studies have thus far limited the offering of NIPT to women at increased risk for fetal aneuploidy, including those:^2–6

• of advanced maternal age
• with a positive conventional screening test
• with abnormal ultrasound results suggestive of aneuploidy, or
• who have had a prior pregnancy with a chromosome aneuploidy found in the NIPT panel.

Studies of all available technologies tested on women at increased risk for fetal aneuploidy have thus far shown considerably higher sensitivities and specificities and detection rates for fetal trisomies 21, 18, and 13 than conventional screening algorithms, although detection rates for trisomy 13 are slightly lower than those observed for trisomies 21 and 18.

WE STILL HAVE MANY HURDLES TO LEAP
However, the groups of women at high risk for fetal aneuploidy just outlined represent only a small segment of the community of pregnant women. A multicenter study involving 1,914 women published February 2014 in the New England Journal of Medicine⁷ showed considerably and significantly lower false-positive rates and higher positive predictive values for the detection of trisomies 21 and 18 by NIPT compared with conventional fetal aneuploidy screening. This study incorporated women at low risk for fetal aneuploidies in the study cohort, although women at high risk (based on the stated range of maternal age) also were included in the cohort. Unfortunately, no information was provided in the report about the percentage of low-risk women among the study participants.

Related articles:
Noninvasive prenatal DNA testing: Who is using it, and how? Audiocast, June 2013
Noninvasive prenatal DNA tests are unproven and costly  David A. Carpenter, MD (Comment & Controversy; September 2013)

Another concern about the published accuracy of NIPT clinical assays was recently sounded by Menutti and colleagues.⁸ The authors cited recent cases of positive NIPT outcomes for fetal trisomies 18 and 13 that were not confirmed by diagnostic testing of the pregnancies in question. The authors pondered whether such cases may reflect a limitation of the positive predictive values attributed to NIPT assays and that such limitations may carry profound inaccuracies in determining the accuracy of such protocols for rare aneuploidies.

While the improved detection rates for NIPT compared with conventional screening are not surprising, guidelines published by the American College of Obstetricians and Gynecologists still do not recommend the use of NIPT for the screening of low-risk women because of insufficient evaluation of ccfna technologies in the screening of such pregnancies.³ This also applies to twin pregnancies, despite preliminary studies showing comparable detection of trisomies 18 and 21 in such pregnancies compared with singleton pregnancies.^3,9

There are no direct comparative studies of the four commercially available screening products, thus precluding a robust comparison and determination of the best existing method to use.

SO, WHERE ARE WE WITH NIPT EXACTLY?
The recent introduction of NIPT into routine obstetric care has left many clinicians with a wide range of questions, many of which cannot be answered because of little or no information, robust or otherwise, to formulate an accurate and cogent response. So let’s state what we know based on the available evidence, recognizing that this will likely change, perhaps considerably, in the weeks and months ahead.

NIPT is a far superior approach, compared with conventional screening approaches, to screening for fetal trisomies 21, 18, and 13 in women carrying singleton pregnancies who are at an increased risk for fetal chromosome abnormalities.

In our current understanding of prenatal screening and diagnosis, NIPT does not provide either the comprehensive approach or the diagnostic accuracy associated with CVS and amniocentesis. As such, NIPT is not a suitable replacement for prenatal diagnostic procedures.

However, its application to screening a low-risk population for the common fetal aneuploidies, as well as in twin pregnancies, has been supported by initial studies, and the inclusion of other clinical outcomes—including other chromosome abnormalities, such as X and Y aneuploidies, trisomy 16, and triploidy^10,11 and certain genomic abnormalities (eg, 22q deletions)—in the screening algorithm will expand the future clinical applications of NIPT screening.

DOES NIPT CHANGE OUR CONCEPTS OF SCREENING AND DIAGNOSIS?
This question is simple but profound and is perhaps the most important to be asked and addressed. Is a screening algorithm that has a similar sensitivity and specificity to that of CVS and amniocentesis for the most common fetal trisomies in the first and second trimesters sufficient to replace invasive testing for most women? Does the ability to detect fetal genomic abnormalities with microarray analyses of fetal cells obtained by CVS or amniocentesis provide a far greater benefit than that possible with any screening algorithm?

With renewed interest in the cost of health-care screening and diagnosis, we need to consider how comprehensive and accurate our prenatal screening and diagnostic tests should be and whether such improvements are desired or even possible from a clinical or economic viewpoint. In addition, the development of new technologies, such as the capture and analysis of fetal cells in maternal blood, presents the potential for a direct diagnostic fetal assay without the risks of an invasive procedure.

BIAS-FREE COUNSELING CANNOT BE OVERLOOKED
That being said, the current role of NIPT and other screening protocols in obstetric care needs to be clearly communicated to women who are considering their fetal assessment options, with emphasis placed on the capabilities and limitations of prenatal screening (even the newer ccfna-based options), the actual risks associated with invasive testing, and the ability of invasive testing to provide expanded fetal information with the use of microarray analyses.

As it has been from the beginning of prenatal testing in the 1960s, counseling continues to be the most important part of the prenatal screening and diagnostic process and it is needed to facilitate clinical decisions made by women and couples. Counseling must include an accurate communication of the risks, benefits, and limitations of the aforementioned options and issues, and should be provided in a manner that strives to be free of bias, direction, and the personal opinions of the counselor.

In order to provide such counseling, we must remain informed of the ongoing work in the field of prenatal testing, a task that has become more challenging with the rapid release of a considerable amount of new information on prenatal screening technologies over the past 2 years. This will likely continue, and perhaps become even more frenetic, with the expected release of additional information on the clinical applications of ccfna technologies in the near future as well as the development of new technologies applicable for the screening and diagnosis of fetal abnormalities.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article. Send your letter to: [email protected] Please include the city and state in which you practice.

The introduction of amniocentesis in the 1960s brought to prenatal diagnosticians the ability to detect fetal chromosome abnormalities and certain structural defects (including neural tube defects). Since that time, a goal for these practitioners has been the development of effective screening algorithms to better identify women at high risk for detectable fetal abnormalities in concert with the advent of safer and more accessible diagnostic tests, with the eventual aim being the development of a noninvasive prenatal diagnostic test.

Postamniocentesis advancements have included the identification of maternal serum analytes as well as the incorporation of first-trimester ultrasonographic measurements of the fetal nuchal translucency (NT) and nasal bone, all associated with an improved ability to identify women at increased risk for fetal trisomies 21 and 18 as well as some other fetal abnormalities. In addition, targeted ultrasound has greatly improved the ability to detect fetal structural and growth abnormalities in women of all risk levels, although it remains a highly subjective process with considerable inter/intraoperator and equipment variability.

Related article: NIPT is expanding rapidly--but don't throw out that CVS kit just yet! (Update on Obstetrics; Jaimey M. Pauli, MD, and John T. Repke, MD; January 2014)

Noninvasive prenatal screening has the advantages of being noninvasive and carrying no increased risk for fetal loss compared with chorionic villus sampling (CVS) and amniocentesis, which are associated with a small increased risk for pregnancy loss (1/500 to 1/1,500 over baseline risk for loss). However, noninvasive screening is limited compared with diagnostic procedures because it provides only a risk adjustment rather than a definitive diagnostic outcome and is mostly limited to assessment for fetal trisomies 18 and 21.

Targeted ultrasound can identify structural abnormalities associated with other chromosomal, genetic, and genomic abnormalities, but again depends on operator experience, equipment used, maternal habitus, and fetal position. Accordingly, considerable interest has remained in developing a more effective approach for detecting fetal aneuploidy and other fetal abnormalities, including assays that eventually could serve to provide noninvasive prenatal diagnosis.

RECENT ADVANCES BRING US CLOSER TO OUR ULTIMATE GOAL
The recent introduction of circulating cell-free nucleic acids (ccfna) technologies for prenatal screening for common fetal aneuploidies, better known as noninvasive prenatal testing, or NIPT, has presented a far more effective prenatal screening protocol for certain groups of women compared with the aforementioned screening algorithms that rely on measurements of the fetal NT in the late first trimester and maternal serum measurements of analytes in the first and second trimesters.

Currently, four NIPT screening products are available commercially in the United States: MaterniT21 Plus (Sequenom, San Diego, California); Verifi (Illumina, San Diego, California); Harmony Prenatal Test (Ariosa Diagnostics, San Jose, California); and Panorama Prenatal Test (Natera, San Carlos, California). While the technologies and algorithms used by each of the companies differ, they all rely on the premise that 5% to 10% of ccfna in maternal blood are fetal in nature.¹ Calculating the ratios of the expected amount of each chromosome-specific nucleic acid to that actually measured in the sample, a prediction of a normal or abnormal complement for that specific chromosome is then made. None of the commercially available tests specifically identify fetal DNA or differentiate fetal from maternal DNA.

Current validation studies have thus far limited the offering of NIPT to women at increased risk for fetal aneuploidy, including those:^2–6

• of advanced maternal age
• with a positive conventional screening test
• with abnormal ultrasound results suggestive of aneuploidy, or
• who have had a prior pregnancy with a chromosome aneuploidy found in the NIPT panel.

Studies of all available technologies tested on women at increased risk for fetal aneuploidy have thus far shown considerably higher sensitivities and specificities and detection rates for fetal trisomies 21, 18, and 13 than conventional screening algorithms, although detection rates for trisomy 13 are slightly lower than those observed for trisomies 21 and 18.

WE STILL HAVE MANY HURDLES TO LEAP
However, the groups of women at high risk for fetal aneuploidy just outlined represent only a small segment of the community of pregnant women. A multicenter study involving 1,914 women published February 2014 in the New England Journal of Medicine⁷ showed considerably and significantly lower false-positive rates and higher positive predictive values for the detection of trisomies 21 and 18 by NIPT compared with conventional fetal aneuploidy screening. This study incorporated women at low risk for fetal aneuploidies in the study cohort, although women at high risk (based on the stated range of maternal age) also were included in the cohort. Unfortunately, no information was provided in the report about the percentage of low-risk women among the study participants.

Related articles:
Noninvasive prenatal DNA testing: Who is using it, and how? Audiocast, June 2013
Noninvasive prenatal DNA tests are unproven and costly  David A. Carpenter, MD (Comment & Controversy; September 2013)

Another concern about the published accuracy of NIPT clinical assays was recently sounded by Menutti and colleagues.⁸ The authors cited recent cases of positive NIPT outcomes for fetal trisomies 18 and 13 that were not confirmed by diagnostic testing of the pregnancies in question. The authors pondered whether such cases may reflect a limitation of the positive predictive values attributed to NIPT assays and that such limitations may carry profound inaccuracies in determining the accuracy of such protocols for rare aneuploidies.

While the improved detection rates for NIPT compared with conventional screening are not surprising, guidelines published by the American College of Obstetricians and Gynecologists still do not recommend the use of NIPT for the screening of low-risk women because of insufficient evaluation of ccfna technologies in the screening of such pregnancies.³ This also applies to twin pregnancies, despite preliminary studies showing comparable detection of trisomies 18 and 21 in such pregnancies compared with singleton pregnancies.^3,9

There are no direct comparative studies of the four commercially available screening products, thus precluding a robust comparison and determination of the best existing method to use.

SO, WHERE ARE WE WITH NIPT EXACTLY?
The recent introduction of NIPT into routine obstetric care has left many clinicians with a wide range of questions, many of which cannot be answered because of little or no information, robust or otherwise, to formulate an accurate and cogent response. So let’s state what we know based on the available evidence, recognizing that this will likely change, perhaps considerably, in the weeks and months ahead.

NIPT is a far superior approach, compared with conventional screening approaches, to screening for fetal trisomies 21, 18, and 13 in women carrying singleton pregnancies who are at an increased risk for fetal chromosome abnormalities.

In our current understanding of prenatal screening and diagnosis, NIPT does not provide either the comprehensive approach or the diagnostic accuracy associated with CVS and amniocentesis. As such, NIPT is not a suitable replacement for prenatal diagnostic procedures.

However, its application to screening a low-risk population for the common fetal aneuploidies, as well as in twin pregnancies, has been supported by initial studies, and the inclusion of other clinical outcomes—including other chromosome abnormalities, such as X and Y aneuploidies, trisomy 16, and triploidy^10,11 and certain genomic abnormalities (eg, 22q deletions)—in the screening algorithm will expand the future clinical applications of NIPT screening.

DOES NIPT CHANGE OUR CONCEPTS OF SCREENING AND DIAGNOSIS?
This question is simple but profound and is perhaps the most important to be asked and addressed. Is a screening algorithm that has a similar sensitivity and specificity to that of CVS and amniocentesis for the most common fetal trisomies in the first and second trimesters sufficient to replace invasive testing for most women? Does the ability to detect fetal genomic abnormalities with microarray analyses of fetal cells obtained by CVS or amniocentesis provide a far greater benefit than that possible with any screening algorithm?

With renewed interest in the cost of health-care screening and diagnosis, we need to consider how comprehensive and accurate our prenatal screening and diagnostic tests should be and whether such improvements are desired or even possible from a clinical or economic viewpoint. In addition, the development of new technologies, such as the capture and analysis of fetal cells in maternal blood, presents the potential for a direct diagnostic fetal assay without the risks of an invasive procedure.

BIAS-FREE COUNSELING CANNOT BE OVERLOOKED
That being said, the current role of NIPT and other screening protocols in obstetric care needs to be clearly communicated to women who are considering their fetal assessment options, with emphasis placed on the capabilities and limitations of prenatal screening (even the newer ccfna-based options), the actual risks associated with invasive testing, and the ability of invasive testing to provide expanded fetal information with the use of microarray analyses.

As it has been from the beginning of prenatal testing in the 1960s, counseling continues to be the most important part of the prenatal screening and diagnostic process and it is needed to facilitate clinical decisions made by women and couples. Counseling must include an accurate communication of the risks, benefits, and limitations of the aforementioned options and issues, and should be provided in a manner that strives to be free of bias, direction, and the personal opinions of the counselor.

In order to provide such counseling, we must remain informed of the ongoing work in the field of prenatal testing, a task that has become more challenging with the rapid release of a considerable amount of new information on prenatal screening technologies over the past 2 years. This will likely continue, and perhaps become even more frenetic, with the expected release of additional information on the clinical applications of ccfna technologies in the near future as well as the development of new technologies applicable for the screening and diagnosis of fetal abnormalities.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article. Send your letter to: [email protected] Please include the city and state in which you practice.

Amniotic fluid embolism (AFE) occurs in about 1 in 20,000 to 1 in 40,000 deliveries.^1,2 Although the condition is rare, the case fatality rate is high, and AFE is a common cause of maternal death in developed countries. AFE cannot be predicted or prevented. Moreover, the condition is difficult to precisely define and is often a diagnosis of exclusion.

AFE should be considered in the differential diagnosis of a pregnant woman with sudden onset of shortness of breath, hypotension, or cardiac arrhythmia or arrest, followed by coagulopathy and hemorrhage. Premonitory symptoms, including restlessness, confusion, disorientation, agitation, chills, nausea, numbness, and tingling, are commonly reported just before the cardiorespiratory collapse. AFE is less likely if the initial obstetric event is hemorrhage in the absence of cardiorespiratory compromise or a preceding coagulopathy.³

Typically, the onset is just before birth, during birth, or within the first few hours after delivery. In the United Kingdom, which has a robust centralized registry for reporting AFE, about 56% of cases occur before birth and 44% after birth.⁴

Related article: Is the incidence of amniotic fluid embolism rising? John T. Repke, MD (Examining the Evidence, August 2010)

The resources available to obstetric units vary greatly. Each unit needs to assess its resources and develop an AFE treatment protocol that builds on the unique strengths of the unit. Treatment of AFE requires the coordinated actions of anesthesiologists, obstetricians, nurses, the blood bank, pharmacy, and cardiovascular specialists. Coordinated activity among the members of such a large multidisciplinary team requires a written protocol that is practiced on a regular basis.

Six important components of a multidisciplinary response to AFE treatment protocol are:

1. high-quality cardiopulmonary resuscitation (CPR)
2. a protocol for massive transfusion
3. treatment of diffuse bleeding and coagulopathy
4. treatment of uterine and pelvic bleeding
5. extracorporeal lung and heart support
6. post-AFE intensive care.

1. Initiate high-quality CPR
Hypotension and hypoxemia due to cardiac and pulmonary dysfunction are prominent features of AFE. Dysrythmias such as pulseless electrical activity, bradycardia, ventricular fibrillation, and asystole are common. Rapid institution of high-quality CPR is critical to the survival of women with AFE.

Interventions often used in CPR of patients with AFE include initiation of high-quality chest compressions, early defibrillation if indicated, immediate administration of 100% oxygen by mask ventilation followed by early intubation, and rapid establishment of peripheral, arterial, and central venous access. Volume assessment, fluid replacement, and administration of vasopressors and inotropes are also important.

CPR of pregnant women requires special interventions, including maximal left lateral displacement of the uterus to reduce compression of the descending aorta and vena cava. Lateral displacement of the uterus can be accomplished by left lateral tilt or by manual uterine displacement. To optimize the effectiveness of chest compressions, many experts recommend placing the woman in a supine position and using manual uterine displacement rather than a left lateral tilt.⁵ For chest compressions, the hands should be placed just above the center of the sternum to adjust for the elevation of the diaphragm caused by the gravid uterus.

The gravid uterus can compromise the effectiveness of CPR. Fetal viability and neurologic outcome are best if delivery occurs within 5 minutes of the onset of cardiopulmonary arrest. If the gestational age of the fetus is consistent with extrauterine viability and initial CPR has not restored cardiac function, it is best to initiate fetal delivery within 4 minutes of the onset of cardiopulmonary arrest with the intent to deliver the fetus within 5 minutes.^6,7 If the fetus is beyond 20 weeks’ gestational age, delivery early in the course of CPR improves the effectiveness of maternal resuscitation and may increase the probability of maternal survival.

In one study of the response of anesthesiologists, obstetricians, and nurses to a simulated cardiac arrest caused by an AFE, the participants did not routinely use defibrillation when indicated, did not place a firm support under the back for chest compressions, and did not switch the provider of chest compressions every 2 minutes.⁸ This study indicates that additional training and routinely scheduled multidisciplinary simulation of the response to cardiopulmonary arrest could improve the quality of our CPR.

2. Use a massive transfusion protocol
Severe coagulopathy and diffuse bleeding are commonly encountered in AFE. Target goals for the replacement of blood products include:

• hemoglobin concentration ≥8 g/dL
• fibrinogen ≥150 to 200 mg/dL
• platelets ≥50,000/μL
• prothrombin time international normalized ratio (INR) ≤1.5.

Most massive transfusion protocols provide for the rapid delivery of 4 to 8 units of red blood cells and a similar number of units of fresh frozen plasma to the patient’s bedside. In the management of AFE, 20 to 30 units of red blood cells and a similar quantity of fresh frozen plasma may need to be transfused. Cryoprecipitate takes 20 to 30 minutes to thaw, so preparations to transfuse cryoprecipitate should be initiated as soon as the massive transfusion protocol is triggered. A case of AFE can completely empty the blood bank of all available blood products and necessitate the use of alternative agents.

Lyophilized fibrinogen concentrate (RiaSTAP) is approved by the US Food and Drug Administration for the treatment of congenital hypofibrinogenemia and also may be useful to replace fibrinogen in cases of AFE. In many hospitals, large quantities of fresh frozen plasma are not immediately available; lyophilized fibrinogen concentrate may be especially useful in these settings. Another advantage of fibrinogen concentrate is that large amounts of fibrinogen can be administered in a small volume of intravenous fluid. Fibrinogen concentrate typically is used at a dose of 70 mg/kg of body weight.^9,10

Intraoperative red cell salvage occasionally is used in cases of obstetric hemorrhage. In one case report of the use of red cell salvage with leukocyte depletion filtration during treatment of an AFE, acute hypotension developed in the patient after the transfusion of salvaged red cells.¹¹ This case report raises safety concerns about the use of salvaged cells in women with severe AFE.

Related article: 10 practical, evidence-based recommendations for the management of severe postpartum hemorrhage  Baha M. Sibai, MD (June 2011)

3. Treat diffuse bleeding and coagulopathy
In addition to the initiation of the massive transfusion protocol, additional treatments that may be helpful in managing the coagulopathy of AFE include tranexamic acid, recombinant factor VIIa (rFVIIa), and exchange transfusion.

AFE is often associated with hyperfibrinolysis, which can cause excessive bleeding.¹² Tranexamic acid blocks the lysine binding sites on plasminogen and thereby reduces the lysis of fibrin clots. Clinical trials in patients who have undergone trauma have demonstrated that the administration of tranexamic acid reduces blood loss.¹³ The dose of tranexamic acid is approximately 10 to 20 mg/kg of body weight, or approximately 1 g.

Controversy exists about the use of rFVIIa to treat the coagulopathy and bleeding caused by AFE. Some authorities believe that rFVIIa is associated with an increased AFE case fatality rate.¹⁴ Other authorities believe rFVIIa may be useful in the treatment of AFE coagulopathy, especially when bleeding persists despite aggressive blood and component replacement.”¹⁵ The dose of rFVIIa is approximately 90 µg/kg of body weight. rFVIIa is extremely expensive.

Exchange transfusion has been used successfully to treat AFE.¹⁶ In women with AFE, exchange transfusion removes circulating cells, cell fragments, and substances that trigger systemic anaphylaxis and coagulopathy, thereby enhancing rapid recovery.

Related article: Act fast when confronted by a coagulopathy postpartum Robert L. Barbieri, MD (Editorial; March 2012)

4. Treat uterine and pelvic bleeding
Obstetrician-gynecologists are experts in the control of uterine and pelvic bleeding. Interventions that commonly are used to control uterine and pelvic bleeding in cases of postpartum hemorrhage, uterine rupture, or placenta accreta also can be applied in cases of AFE with uncontrolled uterine and pelvic bleeding. These techniques include:

• use of uterine compression sutures
• the Bakri balloon
• a uterine tourniquet
• vascular clamps on the ovarian vessels.^17,18

In many cases of AFE, total or supracervical hysterectomy is necessary to control uterine bleeding. Uterine artery embolization, if available, has been reported to be helpful in select cases. However, many women with AFE are too unstable to survive transfer to an interventional radiology suite. Additional interventions to control bleeding include hypogastric artery ligation, infrarenal aortic compression, and pelvic packing.

Cross-clamping the aorta below the renal vessels can reduce blood flow to the pelvis and provide time for cardiopulmonary and volume resuscitation. Alternatively, placing pressure on the infrarenal aorta with a sponge or directly by hand can help reduce blood flow to the pelvis.¹⁹

In many cases of AFE, pelvic hemorrhage is difficult to control. Even if surgical pedicles are ligated securely, the coagulopathy of AFE may cause persistent oozing from areas of minor tissue trauma. Uncontrolled blood loss can be a proximate cause of death in women with AFE. All written protocols for responding to an AFE should include a plan to use pelvic packing for patients in whom standard operative procedures do not produce adequate control of bleeding. A “mushroom,” “parachute,” or “umbrella” pack has been reported to help stabilize the severely ill patient with pelvic bleeding and permit effective resuscitation and blood product replacement.²⁰

Related articles:
A stitch in time: The B-Lynch, Hayman and Pereira uterine compression sutures Robert L. Barbieri, MD (Editorial, December 2012)
Have you made the best use of the Bakri balloon in PPH? Robert L. Barbieri, MD (Editorial, July 2011)

5. Consider extracorporeal lung and heart support
In many cases of AFE, both lung and cardiac function are severely compromised. Both veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and full cardiopulmonary bypass provide support for the failing lung and heart. Based on a small number of case reports, extracorporeal lung and heart support appear to be useful in the treatment of AFE.^21–26 Using the Seldinger technique,²⁷ it is technically feasible to rapidly access a major vein and artery to provide the input and output ports for VA-ECMO. Unlike the cardiopulmonary bypass pump, the VA-ECMO pump does not have a reservoir that needs to be primed with blood and is smaller and more portable. To provide a patient with VA-ECMO or cardiopulmonary bypass, a cardiac interventionist and a perfusionist must be available. Extracorporeal lung and heart support require heparinization of the patient’s blood, which may result in increased bleeding. Both VA-ECMO and cardiopulmonary bypass, along with the diseases for which they are used, may cause renal dysfunction, neurologic injury, and infection.²⁸

Alternative approaches that provide support of the heart—but not lung—are the Impella pump, TandemHeart, and the intra-aortic balloon pump. An alternative that provides lung support—but not cardiac support—is veno-venous ECMO.

In developing a written protocol for responding to an AFE, obstetricians should explore the potential availability of VA-ECMO, cardiopulmonary bypass, or other cardiopulmonary support devices as options for patients who have not responded to standard treatment of AFE and are at high risk of death.

6. Post-AFE intensive care
After stabilization, most women with AFE will require intensive care for 48 to 96 hours. Some experts have proposed that all survivors of cardiopulmonary arrest who are successfully resuscitated and stabilized be transferred to hospitals that specialize in post−cardiac arrest care to improve outcomes.

Assessment of organ injury is important after an AFE. In addition, encephalopathy is a common complication of AFE, and sequential neurologic examination is a priority. Therapeutic hypothermia (TH) may help to preserve neurologic function after AFE.²⁹ However, TH may cause a mild coagulopathy by inhibiting platelet activation and enzyme activity of clotting factors. Because coagulopathy is a prominent feature of AFE, TH may be contraindicated if the patient has a clinically significant baseline coagulopathy.³⁰

DEVELOP AN AFE PROTOCOL AND PRACTICE THE COMPONENTS
Practicing the components of obstetric protocols can improve unit performance and patient outcomes.³¹ The components of an AFE protocol, as described in this article, include high-quality CPR, a protocol for massive transfusion, treatment of diffuse bleeding and coagulopathy, treatment of uterine and pelvic bleeding, extracorporeal lung and heart support, and post-AFE intensive care. Practicing these components of an AFE protocol will enhance performance across many common obstetric complications including postpartum hemorrhage, uterine rupture, placenta accreta, and pulmonary embolism.

When Chesley “Sully” Sullenberger and his copilot landed Flight 1549 in the Hudson River in New York, he had never practiced that specific response to twin engine failure, but he had practiced many emergency responses involving related scenarios. The combination of exceptional flight experience and years of practicing the response to emergency scenarios in simulation exercises permitted him and his copilot to execute a uniquely clever plan to solve a life-threatening
emergency. In a related way, practicing the components of AFE treatment will help obstetricians, obstetric anesthesiologists, and their multidisciplinary team to improve the responses to all major obstetric emergencies. 

INSTANT POLL
Does your obstetric unit have a written protocol for treating an amniotic fluid embolism (AFE)? Has your obstetric unit practiced any of the components of the AFE treatment protocol: 1) high-quality cardiopulmonary resuscitation, 2) a protocol for massive transfusion protocol, 3) treatment of diffuse bleeding and coagulopathy, 4) treatment of uterine and pelvic bleeding, 5) extracorporeal lung and heart support, and 6) post-AFE intensive care?
Tell us—at [email protected]. Please include your name and the city and state in which you practice.

Amniotic fluid embolism (AFE) occurs in about 1 in 20,000 to 1 in 40,000 deliveries.^1,2 Although the condition is rare, the case fatality rate is high, and AFE is a common cause of maternal death in developed countries. AFE cannot be predicted or prevented. Moreover, the condition is difficult to precisely define and is often a diagnosis of exclusion.

AFE should be considered in the differential diagnosis of a pregnant woman with sudden onset of shortness of breath, hypotension, or cardiac arrhythmia or arrest, followed by coagulopathy and hemorrhage. Premonitory symptoms, including restlessness, confusion, disorientation, agitation, chills, nausea, numbness, and tingling, are commonly reported just before the cardiorespiratory collapse. AFE is less likely if the initial obstetric event is hemorrhage in the absence of cardiorespiratory compromise or a preceding coagulopathy.³

Typically, the onset is just before birth, during birth, or within the first few hours after delivery. In the United Kingdom, which has a robust centralized registry for reporting AFE, about 56% of cases occur before birth and 44% after birth.⁴

Related article: Is the incidence of amniotic fluid embolism rising? John T. Repke, MD (Examining the Evidence, August 2010)

The resources available to obstetric units vary greatly. Each unit needs to assess its resources and develop an AFE treatment protocol that builds on the unique strengths of the unit. Treatment of AFE requires the coordinated actions of anesthesiologists, obstetricians, nurses, the blood bank, pharmacy, and cardiovascular specialists. Coordinated activity among the members of such a large multidisciplinary team requires a written protocol that is practiced on a regular basis.

Six important components of a multidisciplinary response to AFE treatment protocol are:

1. high-quality cardiopulmonary resuscitation (CPR)
2. a protocol for massive transfusion
3. treatment of diffuse bleeding and coagulopathy
4. treatment of uterine and pelvic bleeding
5. extracorporeal lung and heart support
6. post-AFE intensive care.

1. Initiate high-quality CPR
Hypotension and hypoxemia due to cardiac and pulmonary dysfunction are prominent features of AFE. Dysrythmias such as pulseless electrical activity, bradycardia, ventricular fibrillation, and asystole are common. Rapid institution of high-quality CPR is critical to the survival of women with AFE.

Interventions often used in CPR of patients with AFE include initiation of high-quality chest compressions, early defibrillation if indicated, immediate administration of 100% oxygen by mask ventilation followed by early intubation, and rapid establishment of peripheral, arterial, and central venous access. Volume assessment, fluid replacement, and administration of vasopressors and inotropes are also important.

CPR of pregnant women requires special interventions, including maximal left lateral displacement of the uterus to reduce compression of the descending aorta and vena cava. Lateral displacement of the uterus can be accomplished by left lateral tilt or by manual uterine displacement. To optimize the effectiveness of chest compressions, many experts recommend placing the woman in a supine position and using manual uterine displacement rather than a left lateral tilt.⁵ For chest compressions, the hands should be placed just above the center of the sternum to adjust for the elevation of the diaphragm caused by the gravid uterus.

The gravid uterus can compromise the effectiveness of CPR. Fetal viability and neurologic outcome are best if delivery occurs within 5 minutes of the onset of cardiopulmonary arrest. If the gestational age of the fetus is consistent with extrauterine viability and initial CPR has not restored cardiac function, it is best to initiate fetal delivery within 4 minutes of the onset of cardiopulmonary arrest with the intent to deliver the fetus within 5 minutes.^6,7 If the fetus is beyond 20 weeks’ gestational age, delivery early in the course of CPR improves the effectiveness of maternal resuscitation and may increase the probability of maternal survival.

In one study of the response of anesthesiologists, obstetricians, and nurses to a simulated cardiac arrest caused by an AFE, the participants did not routinely use defibrillation when indicated, did not place a firm support under the back for chest compressions, and did not switch the provider of chest compressions every 2 minutes.⁸ This study indicates that additional training and routinely scheduled multidisciplinary simulation of the response to cardiopulmonary arrest could improve the quality of our CPR.

2. Use a massive transfusion protocol
Severe coagulopathy and diffuse bleeding are commonly encountered in AFE. Target goals for the replacement of blood products include:

• hemoglobin concentration ≥8 g/dL
• fibrinogen ≥150 to 200 mg/dL
• platelets ≥50,000/μL
• prothrombin time international normalized ratio (INR) ≤1.5.

Most massive transfusion protocols provide for the rapid delivery of 4 to 8 units of red blood cells and a similar number of units of fresh frozen plasma to the patient’s bedside. In the management of AFE, 20 to 30 units of red blood cells and a similar quantity of fresh frozen plasma may need to be transfused. Cryoprecipitate takes 20 to 30 minutes to thaw, so preparations to transfuse cryoprecipitate should be initiated as soon as the massive transfusion protocol is triggered. A case of AFE can completely empty the blood bank of all available blood products and necessitate the use of alternative agents.

Lyophilized fibrinogen concentrate (RiaSTAP) is approved by the US Food and Drug Administration for the treatment of congenital hypofibrinogenemia and also may be useful to replace fibrinogen in cases of AFE. In many hospitals, large quantities of fresh frozen plasma are not immediately available; lyophilized fibrinogen concentrate may be especially useful in these settings. Another advantage of fibrinogen concentrate is that large amounts of fibrinogen can be administered in a small volume of intravenous fluid. Fibrinogen concentrate typically is used at a dose of 70 mg/kg of body weight.^9,10

Intraoperative red cell salvage occasionally is used in cases of obstetric hemorrhage. In one case report of the use of red cell salvage with leukocyte depletion filtration during treatment of an AFE, acute hypotension developed in the patient after the transfusion of salvaged red cells.¹¹ This case report raises safety concerns about the use of salvaged cells in women with severe AFE.

Related article: 10 practical, evidence-based recommendations for the management of severe postpartum hemorrhage  Baha M. Sibai, MD (June 2011)

3. Treat diffuse bleeding and coagulopathy
In addition to the initiation of the massive transfusion protocol, additional treatments that may be helpful in managing the coagulopathy of AFE include tranexamic acid, recombinant factor VIIa (rFVIIa), and exchange transfusion.

AFE is often associated with hyperfibrinolysis, which can cause excessive bleeding.¹² Tranexamic acid blocks the lysine binding sites on plasminogen and thereby reduces the lysis of fibrin clots. Clinical trials in patients who have undergone trauma have demonstrated that the administration of tranexamic acid reduces blood loss.¹³ The dose of tranexamic acid is approximately 10 to 20 mg/kg of body weight, or approximately 1 g.

Controversy exists about the use of rFVIIa to treat the coagulopathy and bleeding caused by AFE. Some authorities believe that rFVIIa is associated with an increased AFE case fatality rate.¹⁴ Other authorities believe rFVIIa may be useful in the treatment of AFE coagulopathy, especially when bleeding persists despite aggressive blood and component replacement.”¹⁵ The dose of rFVIIa is approximately 90 µg/kg of body weight. rFVIIa is extremely expensive.

Exchange transfusion has been used successfully to treat AFE.¹⁶ In women with AFE, exchange transfusion removes circulating cells, cell fragments, and substances that trigger systemic anaphylaxis and coagulopathy, thereby enhancing rapid recovery.

Related article: Act fast when confronted by a coagulopathy postpartum Robert L. Barbieri, MD (Editorial; March 2012)

4. Treat uterine and pelvic bleeding
Obstetrician-gynecologists are experts in the control of uterine and pelvic bleeding. Interventions that commonly are used to control uterine and pelvic bleeding in cases of postpartum hemorrhage, uterine rupture, or placenta accreta also can be applied in cases of AFE with uncontrolled uterine and pelvic bleeding. These techniques include:

• use of uterine compression sutures
• the Bakri balloon
• a uterine tourniquet
• vascular clamps on the ovarian vessels.^17,18

In many cases of AFE, total or supracervical hysterectomy is necessary to control uterine bleeding. Uterine artery embolization, if available, has been reported to be helpful in select cases. However, many women with AFE are too unstable to survive transfer to an interventional radiology suite. Additional interventions to control bleeding include hypogastric artery ligation, infrarenal aortic compression, and pelvic packing.

Cross-clamping the aorta below the renal vessels can reduce blood flow to the pelvis and provide time for cardiopulmonary and volume resuscitation. Alternatively, placing pressure on the infrarenal aorta with a sponge or directly by hand can help reduce blood flow to the pelvis.¹⁹

In many cases of AFE, pelvic hemorrhage is difficult to control. Even if surgical pedicles are ligated securely, the coagulopathy of AFE may cause persistent oozing from areas of minor tissue trauma. Uncontrolled blood loss can be a proximate cause of death in women with AFE. All written protocols for responding to an AFE should include a plan to use pelvic packing for patients in whom standard operative procedures do not produce adequate control of bleeding. A “mushroom,” “parachute,” or “umbrella” pack has been reported to help stabilize the severely ill patient with pelvic bleeding and permit effective resuscitation and blood product replacement.²⁰

Related articles:
A stitch in time: The B-Lynch, Hayman and Pereira uterine compression sutures Robert L. Barbieri, MD (Editorial, December 2012)
Have you made the best use of the Bakri balloon in PPH? Robert L. Barbieri, MD (Editorial, July 2011)

5. Consider extracorporeal lung and heart support
In many cases of AFE, both lung and cardiac function are severely compromised. Both veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and full cardiopulmonary bypass provide support for the failing lung and heart. Based on a small number of case reports, extracorporeal lung and heart support appear to be useful in the treatment of AFE.^21–26 Using the Seldinger technique,²⁷ it is technically feasible to rapidly access a major vein and artery to provide the input and output ports for VA-ECMO. Unlike the cardiopulmonary bypass pump, the VA-ECMO pump does not have a reservoir that needs to be primed with blood and is smaller and more portable. To provide a patient with VA-ECMO or cardiopulmonary bypass, a cardiac interventionist and a perfusionist must be available. Extracorporeal lung and heart support require heparinization of the patient’s blood, which may result in increased bleeding. Both VA-ECMO and cardiopulmonary bypass, along with the diseases for which they are used, may cause renal dysfunction, neurologic injury, and infection.²⁸

Alternative approaches that provide support of the heart—but not lung—are the Impella pump, TandemHeart, and the intra-aortic balloon pump. An alternative that provides lung support—but not cardiac support—is veno-venous ECMO.

In developing a written protocol for responding to an AFE, obstetricians should explore the potential availability of VA-ECMO, cardiopulmonary bypass, or other cardiopulmonary support devices as options for patients who have not responded to standard treatment of AFE and are at high risk of death.

6. Post-AFE intensive care
After stabilization, most women with AFE will require intensive care for 48 to 96 hours. Some experts have proposed that all survivors of cardiopulmonary arrest who are successfully resuscitated and stabilized be transferred to hospitals that specialize in post−cardiac arrest care to improve outcomes.

Assessment of organ injury is important after an AFE. In addition, encephalopathy is a common complication of AFE, and sequential neurologic examination is a priority. Therapeutic hypothermia (TH) may help to preserve neurologic function after AFE.²⁹ However, TH may cause a mild coagulopathy by inhibiting platelet activation and enzyme activity of clotting factors. Because coagulopathy is a prominent feature of AFE, TH may be contraindicated if the patient has a clinically significant baseline coagulopathy.³⁰

DEVELOP AN AFE PROTOCOL AND PRACTICE THE COMPONENTS
Practicing the components of obstetric protocols can improve unit performance and patient outcomes.³¹ The components of an AFE protocol, as described in this article, include high-quality CPR, a protocol for massive transfusion, treatment of diffuse bleeding and coagulopathy, treatment of uterine and pelvic bleeding, extracorporeal lung and heart support, and post-AFE intensive care. Practicing these components of an AFE protocol will enhance performance across many common obstetric complications including postpartum hemorrhage, uterine rupture, placenta accreta, and pulmonary embolism.

When Chesley “Sully” Sullenberger and his copilot landed Flight 1549 in the Hudson River in New York, he had never practiced that specific response to twin engine failure, but he had practiced many emergency responses involving related scenarios. The combination of exceptional flight experience and years of practicing the response to emergency scenarios in simulation exercises permitted him and his copilot to execute a uniquely clever plan to solve a life-threatening
emergency. In a related way, practicing the components of AFE treatment will help obstetricians, obstetric anesthesiologists, and their multidisciplinary team to improve the responses to all major obstetric emergencies. 

INSTANT POLL
Does your obstetric unit have a written protocol for treating an amniotic fluid embolism (AFE)? Has your obstetric unit practiced any of the components of the AFE treatment protocol: 1) high-quality cardiopulmonary resuscitation, 2) a protocol for massive transfusion protocol, 3) treatment of diffuse bleeding and coagulopathy, 4) treatment of uterine and pelvic bleeding, 5) extracorporeal lung and heart support, and 6) post-AFE intensive care?
Tell us—at [email protected]. Please include your name and the city and state in which you practice.

Amniotic fluid embolism (AFE) occurs in about 1 in 20,000 to 1 in 40,000 deliveries.^1,2 Although the condition is rare, the case fatality rate is high, and AFE is a common cause of maternal death in developed countries. AFE cannot be predicted or prevented. Moreover, the condition is difficult to precisely define and is often a diagnosis of exclusion.

AFE should be considered in the differential diagnosis of a pregnant woman with sudden onset of shortness of breath, hypotension, or cardiac arrhythmia or arrest, followed by coagulopathy and hemorrhage. Premonitory symptoms, including restlessness, confusion, disorientation, agitation, chills, nausea, numbness, and tingling, are commonly reported just before the cardiorespiratory collapse. AFE is less likely if the initial obstetric event is hemorrhage in the absence of cardiorespiratory compromise or a preceding coagulopathy.³

Typically, the onset is just before birth, during birth, or within the first few hours after delivery. In the United Kingdom, which has a robust centralized registry for reporting AFE, about 56% of cases occur before birth and 44% after birth.⁴

Related article: Is the incidence of amniotic fluid embolism rising? John T. Repke, MD (Examining the Evidence, August 2010)

The resources available to obstetric units vary greatly. Each unit needs to assess its resources and develop an AFE treatment protocol that builds on the unique strengths of the unit. Treatment of AFE requires the coordinated actions of anesthesiologists, obstetricians, nurses, the blood bank, pharmacy, and cardiovascular specialists. Coordinated activity among the members of such a large multidisciplinary team requires a written protocol that is practiced on a regular basis.

Six important components of a multidisciplinary response to AFE treatment protocol are:

1. high-quality cardiopulmonary resuscitation (CPR)
2. a protocol for massive transfusion
3. treatment of diffuse bleeding and coagulopathy
4. treatment of uterine and pelvic bleeding
5. extracorporeal lung and heart support
6. post-AFE intensive care.

1. Initiate high-quality CPR
Hypotension and hypoxemia due to cardiac and pulmonary dysfunction are prominent features of AFE. Dysrythmias such as pulseless electrical activity, bradycardia, ventricular fibrillation, and asystole are common. Rapid institution of high-quality CPR is critical to the survival of women with AFE.