Clinical Review

The term osteoma cutis (OC) is defined as the ossification or bone formation either in the dermis or hypodermis. ¹ It is heterotopic in nature, referring to extraneous bone formation in soft tissue. Osteoma cutis was first described in 1858 ^2,3 ; in 1868, the multiple miliary form on the face was described. ⁴ Cutaneous ossification can take many forms, ranging from occurrence in a nevus (nevus of Nanta) to its association with rare genetic disorders, such as fibrodysplasia ossificans progressiva and Albright hereditary osteodystrophy.

Some of these ossifications are classified as primary; others are secondary, depending on the presence of a preexisting lesion (eg, pilomatricoma, basal cell carcinoma). However, certain conditions, such as multiple miliary osteoma of the face, can be difficult to classify due to the presence or absence of a history of acne or dermabrasion, or both. The secondary forms more commonly are encountered due to their incidental association with an excised lesion, such as pilomatricoma.

A precursor of OC has been neglected in the literature despite its common occurrence. It may have been peripherally alluded to in the literature in reference to the miliary form of OC.^5,6 The cases reported here demonstrate small round nodules of calcification or ossification, or both, in punch biopsies and excision specimens from hair-bearing areas of skin, especially from the head and neck. These lesions are mainly observed in the peripilar location or more specifically in the approximate location of the hair bulb.

This article reviews a possible mechanism of formation of these osteocalcific micronodules. These often-encountered micronodules are small osteocalcific lesions without typical bone or well-formed OC, such as trabeculae formation or fatty marrow, and may represent earliest stages in the formation of OC.

Clinical Observations

During routine dermatopathologic practice, I observed incidental small osteocalcific micronodules in close proximity to the lower part of the hair follicle in multiple cases. These nodules were not related to the main lesion in the specimen and were not the reason for the biopsy or excision. Most of the time, these micronodules were noted in excision or re-excision specimens or in a punch biopsy.

In my review of multiple unrelated cases over time, incidental osteocalcific micronodules were observed occasionally in punch biopsies and excision specimens during routine practice. These micronodules were mainly located in the vicinity of a hair bulb (Figure 1). If the hair bulb was not present in the sections, these micronodules were noted near or within the fibrous tract (Figure 2) or beneath a sebaceous lobule (Figure 3). In an exceptional case, a small round deposit of osteoid was seen forming just above the dermal papilla of the hair bulb (Figure 4).

Multiple osteocalcific micronodules were identified in a case of cicatricial alopecia. These micronodules were observed in sections taken at the levels of hair bulbs, and more or less corresponded to the size of the bulb (Figure 5A). Fortuitously, the patient was dark-skinned; the remnants of melanin within the micronodules provided evidence that the micronodules were formed within hair bulbs. Melanin staining confirmed the presence of melanin within some of the micronodules (Figure 5B).

Comment

Skeletogenesis in humans takes place by 2 methods: endochondral ossification and intramembranous ossification. In contrast to endochondral ossification, intramembranous ossification does not require a preexisting cartilaginous template. Instead, there is condensation of mesenchymal cells, which differentiate into osteoblasts and lay down osteoid, thus forming an ossification center. Little is known about the mechanism of formation of OC or the nidus of formation of the primary form.

Incidental micronodules of calcification and ossification are routinely encountered during histopathologic review of specimens from hair-bearing areas of the skin in dermatopathology practice. A review of the literature, however, does not reveal any specific dermatopathologic term ascribed to this phenomenon. These lesions might be similar to those described by Hopkins⁵ in 1928 in the setting of miliary OC of the face secondary to acne. Rossman and Freeman⁶ also described the same lesions when referring to facial OC as a “stage of pre-osseous calcification.”

When these osteocalcific micronodules are encountered, it usually is in close proximity to a hair follicle bulb. When a hair bulb is not seen in the sections, the micronodules are noted near fibrous tracts, arrector pili muscles, or sebaceous lobules, suggesting a close peripilar or peribulbar location. The micronodules are approximately 0.5 mm in diameter—roughly the size of a hair bulb. Due to the close anatomic association of micronodules and the hair bulb, these lesions can be called pilar osteocalcific nodules (PONs).

The role of bone morphogenetic protein (BMP) signaling in the maintenance of the hair cycle is well established. Bone morphogenetic proteins are extracellular cytokines that belong to the transforming growth factor β family. The hair bulb microenvironment is rich in BMPs, which are essential in cross-talk between hair matrix cells and follicular dermal papilla (FDP) cells in the maintenance of the hair cycle, especially during cytodifferentiation.⁷ Follicular dermal papilla cells lose their hair follicle inductive properties in vitro in the absence of BMP signaling. Introducing BMP to the in vitro niche restores these molecular properties of FDP cells.⁸

As the name implies, BMPs were discovered in relation to their important role in osteogenesis and tissue homeostasis. More than 20 BMPs have been identified, many of which promote bone formation and repair of bone fracture. Osteoinductive BMPs include BMP-2 and BMP-4 through BMP-10; BMP-2 and BMP-4 are expressed in the hair matrix and BMP-4 and BMP-6 are expressed in the FDP.^8,9 All bone-inducing BMPs can cause mesenchymal stem cells to differentiate into osteoblasts in vitro.¹⁰

Overactive BMP signaling has been shown to cause heterotopic ossification in patients with fibrodysplasia ossificans progressiva.⁸ Immunohistochemical expression of BMP-2 has been demonstrated in shadow cells of pilomatricoma.¹¹ Calcification and ossification are seen in as many as 20% of pilomatricomas. Both BMP-2 and BMP-4 have been shown to induce osteogenic differentiation of mouse skin−derived fibroblasts and FDP cells.¹²

Myllylä et al¹³ described 4 cases of multiple miliary osteoma cutis (MMOC). They also found 47 reported cases of MMOC, in which there was a history of acne in 55% (26/47). Only 15% (7/47) of these cases were extrafacial on the neck, chest, back, and arms. Osteomas in these cases were not associated with folliculosebaceous units or other adnexal structures, which may have been due to replacement by acne scarring, as all 4 patients had a history of acne vulgaris. The authors postulated a role for the GNAS gene mutation in the morphogenesis of MMOC; however, no supporting evidence was found for this claim. They also postulated a role for BMPs in the formation of MMOC.¹³

Another interesting aspect of osteoma formation in human skin is the similarity to osteoderms or the integumentary skeleton of vertebrates.¹⁴ Early in evolution, the dermal skeleton was the predominant skeletal system in some lineages. Phylogenetically, osteoderms are not uniformly distributed, and show a latent ability to manifest in some groups or lay dormant or disappear in others. The occurrence of primary osteomas in the human integument might be a vestigial manifestation of deep homology,¹⁵ a latent ability to form structures that have been lost. The embryologic formation of osteoderms in the dermis of vertebrates is thought to depend on the interaction or cross-talk between ectomesenchymal cells of neural crest origin and cells of the stratum basalis of epidermis, which is somewhat similar to the formation of the hair follicles.

Conclusion

Under certain conditions, the bulb region of a hair follicle might provide a nidus for the formation of OC. The hair bulb region contains both the precursor cellular element (mesenchymal cells of FDP) and the trigger cytokine (BMP) for the induction of osteogenic metaplasia.

The term osteoma cutis (OC) is defined as the ossification or bone formation either in the dermis or hypodermis. ¹ It is heterotopic in nature, referring to extraneous bone formation in soft tissue. Osteoma cutis was first described in 1858 ^2,3 ; in 1868, the multiple miliary form on the face was described. ⁴ Cutaneous ossification can take many forms, ranging from occurrence in a nevus (nevus of Nanta) to its association with rare genetic disorders, such as fibrodysplasia ossificans progressiva and Albright hereditary osteodystrophy.

Some of these ossifications are classified as primary; others are secondary, depending on the presence of a preexisting lesion (eg, pilomatricoma, basal cell carcinoma). However, certain conditions, such as multiple miliary osteoma of the face, can be difficult to classify due to the presence or absence of a history of acne or dermabrasion, or both. The secondary forms more commonly are encountered due to their incidental association with an excised lesion, such as pilomatricoma.

A precursor of OC has been neglected in the literature despite its common occurrence. It may have been peripherally alluded to in the literature in reference to the miliary form of OC.^5,6 The cases reported here demonstrate small round nodules of calcification or ossification, or both, in punch biopsies and excision specimens from hair-bearing areas of skin, especially from the head and neck. These lesions are mainly observed in the peripilar location or more specifically in the approximate location of the hair bulb.

This article reviews a possible mechanism of formation of these osteocalcific micronodules. These often-encountered micronodules are small osteocalcific lesions without typical bone or well-formed OC, such as trabeculae formation or fatty marrow, and may represent earliest stages in the formation of OC.

Clinical Observations

During routine dermatopathologic practice, I observed incidental small osteocalcific micronodules in close proximity to the lower part of the hair follicle in multiple cases. These nodules were not related to the main lesion in the specimen and were not the reason for the biopsy or excision. Most of the time, these micronodules were noted in excision or re-excision specimens or in a punch biopsy.

In my review of multiple unrelated cases over time, incidental osteocalcific micronodules were observed occasionally in punch biopsies and excision specimens during routine practice. These micronodules were mainly located in the vicinity of a hair bulb (Figure 1). If the hair bulb was not present in the sections, these micronodules were noted near or within the fibrous tract (Figure 2) or beneath a sebaceous lobule (Figure 3). In an exceptional case, a small round deposit of osteoid was seen forming just above the dermal papilla of the hair bulb (Figure 4).

Multiple osteocalcific micronodules were identified in a case of cicatricial alopecia. These micronodules were observed in sections taken at the levels of hair bulbs, and more or less corresponded to the size of the bulb (Figure 5A). Fortuitously, the patient was dark-skinned; the remnants of melanin within the micronodules provided evidence that the micronodules were formed within hair bulbs. Melanin staining confirmed the presence of melanin within some of the micronodules (Figure 5B).

Comment

Skeletogenesis in humans takes place by 2 methods: endochondral ossification and intramembranous ossification. In contrast to endochondral ossification, intramembranous ossification does not require a preexisting cartilaginous template. Instead, there is condensation of mesenchymal cells, which differentiate into osteoblasts and lay down osteoid, thus forming an ossification center. Little is known about the mechanism of formation of OC or the nidus of formation of the primary form.

Incidental micronodules of calcification and ossification are routinely encountered during histopathologic review of specimens from hair-bearing areas of the skin in dermatopathology practice. A review of the literature, however, does not reveal any specific dermatopathologic term ascribed to this phenomenon. These lesions might be similar to those described by Hopkins⁵ in 1928 in the setting of miliary OC of the face secondary to acne. Rossman and Freeman⁶ also described the same lesions when referring to facial OC as a “stage of pre-osseous calcification.”

When these osteocalcific micronodules are encountered, it usually is in close proximity to a hair follicle bulb. When a hair bulb is not seen in the sections, the micronodules are noted near fibrous tracts, arrector pili muscles, or sebaceous lobules, suggesting a close peripilar or peribulbar location. The micronodules are approximately 0.5 mm in diameter—roughly the size of a hair bulb. Due to the close anatomic association of micronodules and the hair bulb, these lesions can be called pilar osteocalcific nodules (PONs).

The role of bone morphogenetic protein (BMP) signaling in the maintenance of the hair cycle is well established. Bone morphogenetic proteins are extracellular cytokines that belong to the transforming growth factor β family. The hair bulb microenvironment is rich in BMPs, which are essential in cross-talk between hair matrix cells and follicular dermal papilla (FDP) cells in the maintenance of the hair cycle, especially during cytodifferentiation.⁷ Follicular dermal papilla cells lose their hair follicle inductive properties in vitro in the absence of BMP signaling. Introducing BMP to the in vitro niche restores these molecular properties of FDP cells.⁸

As the name implies, BMPs were discovered in relation to their important role in osteogenesis and tissue homeostasis. More than 20 BMPs have been identified, many of which promote bone formation and repair of bone fracture. Osteoinductive BMPs include BMP-2 and BMP-4 through BMP-10; BMP-2 and BMP-4 are expressed in the hair matrix and BMP-4 and BMP-6 are expressed in the FDP.^8,9 All bone-inducing BMPs can cause mesenchymal stem cells to differentiate into osteoblasts in vitro.¹⁰

Overactive BMP signaling has been shown to cause heterotopic ossification in patients with fibrodysplasia ossificans progressiva.⁸ Immunohistochemical expression of BMP-2 has been demonstrated in shadow cells of pilomatricoma.¹¹ Calcification and ossification are seen in as many as 20% of pilomatricomas. Both BMP-2 and BMP-4 have been shown to induce osteogenic differentiation of mouse skin−derived fibroblasts and FDP cells.¹²

Myllylä et al¹³ described 4 cases of multiple miliary osteoma cutis (MMOC). They also found 47 reported cases of MMOC, in which there was a history of acne in 55% (26/47). Only 15% (7/47) of these cases were extrafacial on the neck, chest, back, and arms. Osteomas in these cases were not associated with folliculosebaceous units or other adnexal structures, which may have been due to replacement by acne scarring, as all 4 patients had a history of acne vulgaris. The authors postulated a role for the GNAS gene mutation in the morphogenesis of MMOC; however, no supporting evidence was found for this claim. They also postulated a role for BMPs in the formation of MMOC.¹³

Another interesting aspect of osteoma formation in human skin is the similarity to osteoderms or the integumentary skeleton of vertebrates.¹⁴ Early in evolution, the dermal skeleton was the predominant skeletal system in some lineages. Phylogenetically, osteoderms are not uniformly distributed, and show a latent ability to manifest in some groups or lay dormant or disappear in others. The occurrence of primary osteomas in the human integument might be a vestigial manifestation of deep homology,¹⁵ a latent ability to form structures that have been lost. The embryologic formation of osteoderms in the dermis of vertebrates is thought to depend on the interaction or cross-talk between ectomesenchymal cells of neural crest origin and cells of the stratum basalis of epidermis, which is somewhat similar to the formation of the hair follicles.

Conclusion

Under certain conditions, the bulb region of a hair follicle might provide a nidus for the formation of OC. The hair bulb region contains both the precursor cellular element (mesenchymal cells of FDP) and the trigger cytokine (BMP) for the induction of osteogenic metaplasia.

The term osteoma cutis (OC) is defined as the ossification or bone formation either in the dermis or hypodermis. ¹ It is heterotopic in nature, referring to extraneous bone formation in soft tissue. Osteoma cutis was first described in 1858 ^2,3 ; in 1868, the multiple miliary form on the face was described. ⁴ Cutaneous ossification can take many forms, ranging from occurrence in a nevus (nevus of Nanta) to its association with rare genetic disorders, such as fibrodysplasia ossificans progressiva and Albright hereditary osteodystrophy.

Some of these ossifications are classified as primary; others are secondary, depending on the presence of a preexisting lesion (eg, pilomatricoma, basal cell carcinoma). However, certain conditions, such as multiple miliary osteoma of the face, can be difficult to classify due to the presence or absence of a history of acne or dermabrasion, or both. The secondary forms more commonly are encountered due to their incidental association with an excised lesion, such as pilomatricoma.

A precursor of OC has been neglected in the literature despite its common occurrence. It may have been peripherally alluded to in the literature in reference to the miliary form of OC.^5,6 The cases reported here demonstrate small round nodules of calcification or ossification, or both, in punch biopsies and excision specimens from hair-bearing areas of skin, especially from the head and neck. These lesions are mainly observed in the peripilar location or more specifically in the approximate location of the hair bulb.

This article reviews a possible mechanism of formation of these osteocalcific micronodules. These often-encountered micronodules are small osteocalcific lesions without typical bone or well-formed OC, such as trabeculae formation or fatty marrow, and may represent earliest stages in the formation of OC.

Clinical Observations

During routine dermatopathologic practice, I observed incidental small osteocalcific micronodules in close proximity to the lower part of the hair follicle in multiple cases. These nodules were not related to the main lesion in the specimen and were not the reason for the biopsy or excision. Most of the time, these micronodules were noted in excision or re-excision specimens or in a punch biopsy.

In my review of multiple unrelated cases over time, incidental osteocalcific micronodules were observed occasionally in punch biopsies and excision specimens during routine practice. These micronodules were mainly located in the vicinity of a hair bulb (Figure 1). If the hair bulb was not present in the sections, these micronodules were noted near or within the fibrous tract (Figure 2) or beneath a sebaceous lobule (Figure 3). In an exceptional case, a small round deposit of osteoid was seen forming just above the dermal papilla of the hair bulb (Figure 4).

Multiple osteocalcific micronodules were identified in a case of cicatricial alopecia. These micronodules were observed in sections taken at the levels of hair bulbs, and more or less corresponded to the size of the bulb (Figure 5A). Fortuitously, the patient was dark-skinned; the remnants of melanin within the micronodules provided evidence that the micronodules were formed within hair bulbs. Melanin staining confirmed the presence of melanin within some of the micronodules (Figure 5B).

Comment

Skeletogenesis in humans takes place by 2 methods: endochondral ossification and intramembranous ossification. In contrast to endochondral ossification, intramembranous ossification does not require a preexisting cartilaginous template. Instead, there is condensation of mesenchymal cells, which differentiate into osteoblasts and lay down osteoid, thus forming an ossification center. Little is known about the mechanism of formation of OC or the nidus of formation of the primary form.

Incidental micronodules of calcification and ossification are routinely encountered during histopathologic review of specimens from hair-bearing areas of the skin in dermatopathology practice. A review of the literature, however, does not reveal any specific dermatopathologic term ascribed to this phenomenon. These lesions might be similar to those described by Hopkins⁵ in 1928 in the setting of miliary OC of the face secondary to acne. Rossman and Freeman⁶ also described the same lesions when referring to facial OC as a “stage of pre-osseous calcification.”

When these osteocalcific micronodules are encountered, it usually is in close proximity to a hair follicle bulb. When a hair bulb is not seen in the sections, the micronodules are noted near fibrous tracts, arrector pili muscles, or sebaceous lobules, suggesting a close peripilar or peribulbar location. The micronodules are approximately 0.5 mm in diameter—roughly the size of a hair bulb. Due to the close anatomic association of micronodules and the hair bulb, these lesions can be called pilar osteocalcific nodules (PONs).

The role of bone morphogenetic protein (BMP) signaling in the maintenance of the hair cycle is well established. Bone morphogenetic proteins are extracellular cytokines that belong to the transforming growth factor β family. The hair bulb microenvironment is rich in BMPs, which are essential in cross-talk between hair matrix cells and follicular dermal papilla (FDP) cells in the maintenance of the hair cycle, especially during cytodifferentiation.⁷ Follicular dermal papilla cells lose their hair follicle inductive properties in vitro in the absence of BMP signaling. Introducing BMP to the in vitro niche restores these molecular properties of FDP cells.⁸

As the name implies, BMPs were discovered in relation to their important role in osteogenesis and tissue homeostasis. More than 20 BMPs have been identified, many of which promote bone formation and repair of bone fracture. Osteoinductive BMPs include BMP-2 and BMP-4 through BMP-10; BMP-2 and BMP-4 are expressed in the hair matrix and BMP-4 and BMP-6 are expressed in the FDP.^8,9 All bone-inducing BMPs can cause mesenchymal stem cells to differentiate into osteoblasts in vitro.¹⁰

Overactive BMP signaling has been shown to cause heterotopic ossification in patients with fibrodysplasia ossificans progressiva.⁸ Immunohistochemical expression of BMP-2 has been demonstrated in shadow cells of pilomatricoma.¹¹ Calcification and ossification are seen in as many as 20% of pilomatricomas. Both BMP-2 and BMP-4 have been shown to induce osteogenic differentiation of mouse skin−derived fibroblasts and FDP cells.¹²

Myllylä et al¹³ described 4 cases of multiple miliary osteoma cutis (MMOC). They also found 47 reported cases of MMOC, in which there was a history of acne in 55% (26/47). Only 15% (7/47) of these cases were extrafacial on the neck, chest, back, and arms. Osteomas in these cases were not associated with folliculosebaceous units or other adnexal structures, which may have been due to replacement by acne scarring, as all 4 patients had a history of acne vulgaris. The authors postulated a role for the GNAS gene mutation in the morphogenesis of MMOC; however, no supporting evidence was found for this claim. They also postulated a role for BMPs in the formation of MMOC.¹³

Another interesting aspect of osteoma formation in human skin is the similarity to osteoderms or the integumentary skeleton of vertebrates.¹⁴ Early in evolution, the dermal skeleton was the predominant skeletal system in some lineages. Phylogenetically, osteoderms are not uniformly distributed, and show a latent ability to manifest in some groups or lay dormant or disappear in others. The occurrence of primary osteomas in the human integument might be a vestigial manifestation of deep homology,¹⁵ a latent ability to form structures that have been lost. The embryologic formation of osteoderms in the dermis of vertebrates is thought to depend on the interaction or cross-talk between ectomesenchymal cells of neural crest origin and cells of the stratum basalis of epidermis, which is somewhat similar to the formation of the hair follicles.

Conclusion

Under certain conditions, the bulb region of a hair follicle might provide a nidus for the formation of OC. The hair bulb region contains both the precursor cellular element (mesenchymal cells of FDP) and the trigger cytokine (BMP) for the induction of osteogenic metaplasia.

The pathogenesis of coronavirus disease 2019 (COVID-19), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not yet completely understood. Thus far, it is known to affect multiple organ systems, including gastrointestinal, neurological, and cardiovascular, with typical clinical symptoms of COVID-19 including fever, cough, myalgia, headache, anosmia, and diarrhea.¹ This multiorgan attack may be secondary to an exaggerated inflammatory reaction with vasculopathy and possibly a hypercoagulable state. Skin manifestations also are prevalent in COVID-19, and they often result in polymorphous presentations.² This article aims to summarize cutaneous clinical signs of COVID-19 so that dermatologists can promptly identify and manage COVID-19 and prevent its spread.

Methods

A PubMed search of articles indexed for MEDLINE was conducted on June 30, 2020. The literature included observational studies, case reports, and literature reviews from January 1, 2020, to June 30, 2020. Search terms included COVID-19, SARS-CoV-2, and coronavirus used in combination with cutaneous, skin, and dermatology. All of the resulting articles were then reviewed for relevance to the cutaneous manifestations of COVID-19. Only confirmed cases of COVID-19 infection were included in this review; suspected unconfirmed cases were excluded. Further exclusion criteria included articles that discussed dermatology in the time of COVID-19 that did not explicitly address its cutaneous manifestations. The remaining literature was evaluated to provide dermatologists and patients with a concise resource for the cutaneous signs and symptoms of COVID-19. Data extracted from the literature included geographic region, number of patients with skin findings, status of COVID-19 infection and timeline, and cutaneous signs. If a cutaneous sign was not given a clear diagnosis in the literature, the senior authors (A.L. and J.J.) assigned it to its most similar classification to aid in ease of understanding and clarity for the readers.

Results

A search of the key terms resulted in 75 articles published in the specified date range. After excluding overtly irrelevant articles and dermatologic conditions in the time of COVID-19 without confirmed SARS-CoV-2 infection, 25 articles ultimately met inclusion criteria. Relevant references from the articles also were explored for cutaneous dermatologic manifestations of COVID-19. Cutaneous manifestations that were repeatedly reported included chilblainlike lesions; acrocyanosis; urticaria; pityriasis rosea–like cutaneous eruption; erythema multiforme–like, vesiculopapular, and morbilliform eruptions; petechiae; livedo reticularis; and purpuric livedo reticularis (dermatologists may label this stellate purpura). Fewer but nonetheless notable cases of androgenic alopecia, periorbital dyschromia, and herpes zoster exacerbations also were documented. The Table summarizes the reported integumentary findings. The eTable groups the common findings and describes patient age, time to onset of cutaneous sign, and any prognostic significance as seen in the literature.

Chilblainlike Lesions and Acrocyanosis
Chilblainlike lesions are edematous eruptions of the fingers and toes. They usually do not scar and are described as erythematous to violaceous papules and macules with possible bullae on the digits. Skin biopsies demonstrate a histopathologic pattern of vacuolar interface dermatitis with necrotic keratinocytes and a thickened basement membrane. Lymphocytic infiltrate presents in a perieccrine distribution, occasionally with plasma cells. The dermatopathologic findings mimic those of chilblain lupus but lack dermal edema.³

These eruptions have been reported in cases of COVID-19 that more frequently affect children and young adults. They usually resolve over the course of viral infection, averaging within 14 days. Chilblainlike eruptions often are associated with pruritus or pain. They commonly are asymmetrical and appear more often on the toes than the fingers.⁴ In cases of COVID-19 that lack systemic symptoms, chilblainlike lesions have been seen on the dorsal fingers as the first presenting sign of infection.⁵

Acral erythema and chilblainlike lesions frequently have been associated with milder infection. Another positive prognostic indicator is the manifestation of these signs in younger individuals.³

Morbilliform Exanthem
The morbilliform exanthem associated with COVID-19 also typically presents in patients with milder disease. It often affects the buttocks, lower abdomen, and thighs, but spares the palms, soles, and mucosae.⁴ This skin sign, which may start out as a generalized morbilliform exanthem, has been seen to morph into macular hemorrhagic purpura on the legs. These cutaneous lesions typically spontaneously resolve.⁸

In a case report by Najarian,⁶ a morbilliform exanthem was seen on the legs, arms, and trunk of a patient who was otherwise asymptomatic but tested positive for COVID-19. The morbilliform exanthem then became confluent on the trunk. Notably, the patient reported pain of the hands and feet.⁶

Another case report described a patient with edematous annular plaques on the palms, neck, and upper extremities who presented solely with fever.⁷ The biopsy specimen was nonspecific but indicated a viral exanthem. Histopathology showed perivascular lymphocytic infiltrate, dermal edema and vacuoles, spongiosis, dyskeratotic basilar keratinocytes, and few neutrophils without eosinophils.⁷

Eczematous Eruption
A confluent eczematous eruption in the flexural areas, the antecubital fossae, and axillary folds has been found in COVID-19 patients.^21,22 An elderly patient with severe COVID-19 developed a squamous erythematous periumbilical patch 1 day after hospital admission. The cutaneous eruption rapidly progressed to digitate scaly plaques on the trunk, thighs, and flank. A biopsy specimen showed epidermal spongiosis, vesicles containing lymphocytes, and Langerhans cells. The upper dermis demonstrated a lymphohistiocytic infiltrate.²³

Pityriasis Rosea–Like Eruption
In Iran, a COVID-19–infected patient developed an erythematous papulosquamous eruption with a herald patch and trailing scales 3 days after viral symptoms, resembling that of pityriasis rosea.²⁴ Nests of Langerhans cells within the epidermis are seen in many viral exanthems, including cases of COVID-19 and pityriasis rosea.²⁵

Urticaria
According to a number of case reports, urticarial lesions have been the first presenting sign of COVID-19 infection, most resolving with antihistamines.^10,11 Some patients with more severe symptoms have had widespread urticaria. An urticarial exanthem appearing on the bilateral thighs and buttocks may be the initial sign of infection.^12,15 Pruritic erythematous plaques over the face and acral areas is another initial sign. Interestingly, pediatric patients have reported nonpruritic urticaria.⁹

Urticaria also has been seen as a late dermatologic sign of viral infection. After battling relentless viral infection for 1 month, a pruritic, confluent, ill-defined eruption appeared along a patient’s trunk, back, and proximal extremities. Histopathologic examination concluded a perivascular lymphocytic infiltrate and dilated vessels in the dermis. The urticaria resolved a week later, and the patient’s nasopharyngeal swab finally came back negative.¹³

Vesiculopapular Eruption
Vesicles mimicking those of chickenpox have been reported. A study of 375 confirmed cases of COVID-19 by Galván Casas et al¹² showed a 9% incidence of this vesicular eruption. A study by Sachdeva et al⁸ revealed vesicular eruptions in 25 of 72 patients. Pruritic papules and vesicles may resemble Grover disease. This cutaneous sign may be seen in the submammary folds, on the hips, or diffusely over the body.

Erythema Multiforme–Like Eruption
Targetoid lesions similar to those of erythema multiforme erupted in 2 of 27 patients with mild COVID-19 infection in a review by Wollina et al.⁴ In a study of 4 patients with erythema multiforme–like eruptions after COVID-19 symptoms resolved, 3 had palatal petechiae. Two of 4 patients had pseudovesicles in the center of the erythematous targetoid patches.²⁶ Targetoid lesions on the extremities have been reported in pediatric patients with COVID-19 infections. These patients often present without any typical viral symptoms but rather just a febrile exanthem or exanthem alone. Thus, to minimize spread of the virus, it is vital to recognize COVID-19 infection early in patients with a viral exanthem during the time of high COVID-19 incidence.⁴

Livedo Reticularis
In the United States, a case series reported 2 patients with transient livedo reticularis throughout the course of COVID-19 infection. The cutaneous eruption resembled erythema ab igne, but there was no history of exposure to heat.¹⁶

Stellate Purpura
In severe COVID-19 infection, a reticulated nonblanching purpura on the buttocks has been reported to demonstrate pauci-inflammatory vascular thrombosis, complement membrane attack complex deposition, and endothelial injury on dermatopathology. Stellate purpura on palmoplantar surfaces also has shown arterial thrombosis in the deep dermis due to complement deposition.¹⁷

Petechiae and Purpura
A morbilliform exanthem may develop into significant petechiae in the popliteal fossae, buttocks, and thighs. A punch biopsy specimen demonstrates a perivascular lymphocytic infiltrate with erythrocyte extravasation and papillary dermal edema with dyskeratotic cells.¹⁸ Purpura of the lower extremities may develop, with histopathology showing fibrinoid necrosis of small vessel walls, neutrophilic infiltrate with karyorrhexis, and granular complement deposition.¹⁹

In Thailand, a patient was misdiagnosed with dengue after presenting with petechiae and low platelet count.²⁰ Further progression of the viral illness resulted in respiratory symptoms. Subsequently, the patient tested positive for COVID-19. This case demonstrates that cutaneous signs of many sorts may be the first presenting signs of COVID-19, even prior to febrile symptoms.²⁰

Androgenic Alopecia
Studies have shown that androgens are related in the pathogenesis of COVID-19. Coronavirus disease 2019 uses a cellular co-receptor, TMPRSS2, which is androgen regulated.²⁷ In a study of 41 males with COVID-19, 29 had androgenic alopecia. However, this is only a correlation, and causation cannot be concluded here. It cannot be determined from this study whether androgenic alopecia is a risk factor, result of COVID-19, or confounder.²⁸

Exaggerated Herpes Zoster
Shors²⁹ reported a herpes zoster eruption in a patient who had symptoms of COVID-19 for 1 week. Further testing confirmed COVID-19 infection, and despite prompt treatment with valacyclovir, the eruption was slow to resolve. The patient then experienced severe postherpetic neuralgia for more than 4 weeks, even with treatment with gabapentin and lidocaine. It is hypothesized that because of the major inflammatory response caused by COVID-19, an exaggerated inflammation occurred in the dorsal root ganglion, resulting in relentless herpes zoster infection.²⁹

Mottled Skin
Born at term, a 15-day-old neonate presented with sepsis and mottling of the skin. The patient did not have any typical COVID-19 symptoms, such as diarrhea or cough, but tested positive for COVID-19.³⁰

Periorbital Dyschromia
Kalner and Vergilis³¹ reported 2 cases of periorbital dyschromia prior to any other COVID-19 infection symptoms. The discoloration improved with resolution of ensuing viral symptoms.³¹

Comment

Many dermatologic signs of COVID-19 have been identified. Their individual frequency and association with viral severity will become more apparent as more cases are reported. So far during this pandemic, common dermatologic manifestations have been polymorphic in clinical presentation.

Onset of Skin Manifestations
The timeline of skin signs and COVID-19 symptoms varies from the first reported sign to weeks after symptom resolution. In the Region of Murcia, Spain, Pérez-Suárez et al¹⁴ collected data on cutaneous signs of patients with COVID-19. Of the patients studied, 9 had tests confirming COVID-19 infection. Truncal urticaria, sacral ulcers, acrocyanosis, and erythema multiforme were all reported in patients more than 2 weeks after symptom onset. One case of tinea infection also was reported 4 days after fever and respiratory symptoms began.¹⁴

Presentation
Coronavirus disease 2019 has affected the skin of both the central thorax and peripheral locations. In a study of 72 patients with cutaneous signs of COVID-19 by Sachdeva et al,⁸ a truncal distribution was most common, but 14 patients reported acral site involvement. Sachdeva et al⁸ reported urticarial reactions in 7 of 72 patients with cutaneous signs. A painful acral cyanosis was seen in 11 of 72 patients. Livedo reticularis presented in 2 patients, and only 1 patient had petechiae. Cutaneous signs were the first indicators of viral infection in 9 of 72 patients; 52 patients presented with respiratory symptoms first. All of the reported cutaneous signs spontaneously resolved within 10 days.⁸

Recalcati³² reviewed 88 patients with COVID-19, and 18 had cutaneous signs at initial onset of viral infection or during hospitalization. The most common integumentary sign reported in this study was erythema, followed by diffuse urticaria, and then a vesicular eruption resembling varicella infection.³²

Some less common phenomena have been identified in patients with COVID-19, including androgenic alopecia, exaggerated herpes zoster and postherpetic neuralgia, mottled skin, and periorbital dyschromia. Being aware of these complications may help in early treatment, diagnosis, and even prevention of viral spread.

Pathogenesis of Skin Manifestations
Few breakthroughs have been made in understanding the pathogenesis of skin manifestations of SARS-CoV-2. Acral ischemia may be a manifestation of COVID-19’s association with hypercoagulation. Increasing fibrinogen and prothrombin times lead to disseminated intravascular coagulation and microthrombi. These tiny blood clots then lodge in blood vessels and cause acral cyanosis and subsequent gangrene.² The proposed mechanism behind this clinical manifestation in younger populations is the hypercoagulable state that COVID-19 creates. Conversely, acral erythema and chilblainlike lesions in older patients are thought to be from acral ischemia as a response to insufficient type 1 interferons. This pathophysiologic mechanism is indicative of a worse prognosis due to the large role that type 1 interferons play in antiviral responses. Coronavirus disease 2019 similarly triggers type 1 interferons; thus, their efficacy positively correlates with good disease prognosis.³

Similarly, the pathogenesis for livedo reticularis in patients with COVID-19 can only be hypothesized. Infected patients are in a hypercoagulable state, and in these cases, it was uncertain whether this was due to a disseminated intravascular coagulation, cold agglutinins, cryofibrinogens, or lupus anticoagulant.¹⁶

Nonetheless, it can be difficult to separate the primary event between vasculopathy or vasculitis in larger vessel pathology specimens. Some of the studies’ pathology reports discuss a granulocytic infiltrate and red blood cell extravasation, which represent small vessel vasculitis. However, the gangrene and necrosing livedo represent vasculopathy events. A final conclusion about the pathogenesis cannot be made without further clinical and histopathologic evaluation.

Histopathology
Biopsy specimens of reported morbilliform eruptions have demonstrated thrombosed vessels with evidence of necrosis and granulocytic infiltrate.²⁵ Another biopsy specimen of a widespread erythematous exanthem demonstrated extravasated red blood cells and vessel wall damage similar to thrombophilic arteritis. Other reports of histopathology showed necrotic keratinocytes and lymphocytic satellitosis at the dermoepidermal junction, resembling Grover disease. These cases demonstrating necrosis suggest a strong cytokine reaction from the virus.²⁵ A concern with these biopsy findings is that morbilliform eruptions generally show dilated vessels with lymphocytes, and these biopsy findings are consistent with a cutaneous small vessel vasculitis. Additionally, histopathologic evaluation of purpuric eruptions has shown erythrocyte extravasation and granulocytic infiltrate indicative of a cutaneous small vessel vasculitis.

Although most reported cases of cutaneous signs of COVID-19 do not have histopathologic reports, Yao et al³³ conducted a dermatopathologic study that investigated the tissue in deceased patients who had COVID-19. This pathology showed hyaline thrombi within the small vessels of the skin, likely leading to the painful acral ischemia. Similarly, Yao et al³³ reported autopsies finding hyaline thrombi within the small vessels of the lungs. More research should be done to explore this pathogenesis as part of prognostic factors and virulence.

Conclusion

Cutaneous signs may be the first reported symptom of COVID-19 infection, and dermatologists should be prepared to identify them. This review may be used as a guide for physicians to quickly identify potential infection as well as further understand the pathogenesis related to COVID-19. Future research is necessary to determine the dermatologic pathogenesis, infectivity, and prevalence of cutaneous manifestations of COVID-19. It also will be important to explore if vasculopathic lesions predict more severe multisystem disease.

The pathogenesis of coronavirus disease 2019 (COVID-19), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not yet completely understood. Thus far, it is known to affect multiple organ systems, including gastrointestinal, neurological, and cardiovascular, with typical clinical symptoms of COVID-19 including fever, cough, myalgia, headache, anosmia, and diarrhea.¹ This multiorgan attack may be secondary to an exaggerated inflammatory reaction with vasculopathy and possibly a hypercoagulable state. Skin manifestations also are prevalent in COVID-19, and they often result in polymorphous presentations.² This article aims to summarize cutaneous clinical signs of COVID-19 so that dermatologists can promptly identify and manage COVID-19 and prevent its spread.

Methods

A PubMed search of articles indexed for MEDLINE was conducted on June 30, 2020. The literature included observational studies, case reports, and literature reviews from January 1, 2020, to June 30, 2020. Search terms included COVID-19, SARS-CoV-2, and coronavirus used in combination with cutaneous, skin, and dermatology. All of the resulting articles were then reviewed for relevance to the cutaneous manifestations of COVID-19. Only confirmed cases of COVID-19 infection were included in this review; suspected unconfirmed cases were excluded. Further exclusion criteria included articles that discussed dermatology in the time of COVID-19 that did not explicitly address its cutaneous manifestations. The remaining literature was evaluated to provide dermatologists and patients with a concise resource for the cutaneous signs and symptoms of COVID-19. Data extracted from the literature included geographic region, number of patients with skin findings, status of COVID-19 infection and timeline, and cutaneous signs. If a cutaneous sign was not given a clear diagnosis in the literature, the senior authors (A.L. and J.J.) assigned it to its most similar classification to aid in ease of understanding and clarity for the readers.

Results

A search of the key terms resulted in 75 articles published in the specified date range. After excluding overtly irrelevant articles and dermatologic conditions in the time of COVID-19 without confirmed SARS-CoV-2 infection, 25 articles ultimately met inclusion criteria. Relevant references from the articles also were explored for cutaneous dermatologic manifestations of COVID-19. Cutaneous manifestations that were repeatedly reported included chilblainlike lesions; acrocyanosis; urticaria; pityriasis rosea–like cutaneous eruption; erythema multiforme–like, vesiculopapular, and morbilliform eruptions; petechiae; livedo reticularis; and purpuric livedo reticularis (dermatologists may label this stellate purpura). Fewer but nonetheless notable cases of androgenic alopecia, periorbital dyschromia, and herpes zoster exacerbations also were documented. The Table summarizes the reported integumentary findings. The eTable groups the common findings and describes patient age, time to onset of cutaneous sign, and any prognostic significance as seen in the literature.

Chilblainlike Lesions and Acrocyanosis
Chilblainlike lesions are edematous eruptions of the fingers and toes. They usually do not scar and are described as erythematous to violaceous papules and macules with possible bullae on the digits. Skin biopsies demonstrate a histopathologic pattern of vacuolar interface dermatitis with necrotic keratinocytes and a thickened basement membrane. Lymphocytic infiltrate presents in a perieccrine distribution, occasionally with plasma cells. The dermatopathologic findings mimic those of chilblain lupus but lack dermal edema.³

These eruptions have been reported in cases of COVID-19 that more frequently affect children and young adults. They usually resolve over the course of viral infection, averaging within 14 days. Chilblainlike eruptions often are associated with pruritus or pain. They commonly are asymmetrical and appear more often on the toes than the fingers.⁴ In cases of COVID-19 that lack systemic symptoms, chilblainlike lesions have been seen on the dorsal fingers as the first presenting sign of infection.⁵

Acral erythema and chilblainlike lesions frequently have been associated with milder infection. Another positive prognostic indicator is the manifestation of these signs in younger individuals.³

Morbilliform Exanthem
The morbilliform exanthem associated with COVID-19 also typically presents in patients with milder disease. It often affects the buttocks, lower abdomen, and thighs, but spares the palms, soles, and mucosae.⁴ This skin sign, which may start out as a generalized morbilliform exanthem, has been seen to morph into macular hemorrhagic purpura on the legs. These cutaneous lesions typically spontaneously resolve.⁸

In a case report by Najarian,⁶ a morbilliform exanthem was seen on the legs, arms, and trunk of a patient who was otherwise asymptomatic but tested positive for COVID-19. The morbilliform exanthem then became confluent on the trunk. Notably, the patient reported pain of the hands and feet.⁶

Another case report described a patient with edematous annular plaques on the palms, neck, and upper extremities who presented solely with fever.⁷ The biopsy specimen was nonspecific but indicated a viral exanthem. Histopathology showed perivascular lymphocytic infiltrate, dermal edema and vacuoles, spongiosis, dyskeratotic basilar keratinocytes, and few neutrophils without eosinophils.⁷

Eczematous Eruption
A confluent eczematous eruption in the flexural areas, the antecubital fossae, and axillary folds has been found in COVID-19 patients.^21,22 An elderly patient with severe COVID-19 developed a squamous erythematous periumbilical patch 1 day after hospital admission. The cutaneous eruption rapidly progressed to digitate scaly plaques on the trunk, thighs, and flank. A biopsy specimen showed epidermal spongiosis, vesicles containing lymphocytes, and Langerhans cells. The upper dermis demonstrated a lymphohistiocytic infiltrate.²³

Pityriasis Rosea–Like Eruption
In Iran, a COVID-19–infected patient developed an erythematous papulosquamous eruption with a herald patch and trailing scales 3 days after viral symptoms, resembling that of pityriasis rosea.²⁴ Nests of Langerhans cells within the epidermis are seen in many viral exanthems, including cases of COVID-19 and pityriasis rosea.²⁵

Urticaria
According to a number of case reports, urticarial lesions have been the first presenting sign of COVID-19 infection, most resolving with antihistamines.^10,11 Some patients with more severe symptoms have had widespread urticaria. An urticarial exanthem appearing on the bilateral thighs and buttocks may be the initial sign of infection.^12,15 Pruritic erythematous plaques over the face and acral areas is another initial sign. Interestingly, pediatric patients have reported nonpruritic urticaria.⁹

Urticaria also has been seen as a late dermatologic sign of viral infection. After battling relentless viral infection for 1 month, a pruritic, confluent, ill-defined eruption appeared along a patient’s trunk, back, and proximal extremities. Histopathologic examination concluded a perivascular lymphocytic infiltrate and dilated vessels in the dermis. The urticaria resolved a week later, and the patient’s nasopharyngeal swab finally came back negative.¹³

Vesiculopapular Eruption
Vesicles mimicking those of chickenpox have been reported. A study of 375 confirmed cases of COVID-19 by Galván Casas et al¹² showed a 9% incidence of this vesicular eruption. A study by Sachdeva et al⁸ revealed vesicular eruptions in 25 of 72 patients. Pruritic papules and vesicles may resemble Grover disease. This cutaneous sign may be seen in the submammary folds, on the hips, or diffusely over the body.

Erythema Multiforme–Like Eruption
Targetoid lesions similar to those of erythema multiforme erupted in 2 of 27 patients with mild COVID-19 infection in a review by Wollina et al.⁴ In a study of 4 patients with erythema multiforme–like eruptions after COVID-19 symptoms resolved, 3 had palatal petechiae. Two of 4 patients had pseudovesicles in the center of the erythematous targetoid patches.²⁶ Targetoid lesions on the extremities have been reported in pediatric patients with COVID-19 infections. These patients often present without any typical viral symptoms but rather just a febrile exanthem or exanthem alone. Thus, to minimize spread of the virus, it is vital to recognize COVID-19 infection early in patients with a viral exanthem during the time of high COVID-19 incidence.⁴

Livedo Reticularis
In the United States, a case series reported 2 patients with transient livedo reticularis throughout the course of COVID-19 infection. The cutaneous eruption resembled erythema ab igne, but there was no history of exposure to heat.¹⁶

Stellate Purpura
In severe COVID-19 infection, a reticulated nonblanching purpura on the buttocks has been reported to demonstrate pauci-inflammatory vascular thrombosis, complement membrane attack complex deposition, and endothelial injury on dermatopathology. Stellate purpura on palmoplantar surfaces also has shown arterial thrombosis in the deep dermis due to complement deposition.¹⁷

Petechiae and Purpura
A morbilliform exanthem may develop into significant petechiae in the popliteal fossae, buttocks, and thighs. A punch biopsy specimen demonstrates a perivascular lymphocytic infiltrate with erythrocyte extravasation and papillary dermal edema with dyskeratotic cells.¹⁸ Purpura of the lower extremities may develop, with histopathology showing fibrinoid necrosis of small vessel walls, neutrophilic infiltrate with karyorrhexis, and granular complement deposition.¹⁹

In Thailand, a patient was misdiagnosed with dengue after presenting with petechiae and low platelet count.²⁰ Further progression of the viral illness resulted in respiratory symptoms. Subsequently, the patient tested positive for COVID-19. This case demonstrates that cutaneous signs of many sorts may be the first presenting signs of COVID-19, even prior to febrile symptoms.²⁰

Androgenic Alopecia
Studies have shown that androgens are related in the pathogenesis of COVID-19. Coronavirus disease 2019 uses a cellular co-receptor, TMPRSS2, which is androgen regulated.²⁷ In a study of 41 males with COVID-19, 29 had androgenic alopecia. However, this is only a correlation, and causation cannot be concluded here. It cannot be determined from this study whether androgenic alopecia is a risk factor, result of COVID-19, or confounder.²⁸

Exaggerated Herpes Zoster
Shors²⁹ reported a herpes zoster eruption in a patient who had symptoms of COVID-19 for 1 week. Further testing confirmed COVID-19 infection, and despite prompt treatment with valacyclovir, the eruption was slow to resolve. The patient then experienced severe postherpetic neuralgia for more than 4 weeks, even with treatment with gabapentin and lidocaine. It is hypothesized that because of the major inflammatory response caused by COVID-19, an exaggerated inflammation occurred in the dorsal root ganglion, resulting in relentless herpes zoster infection.²⁹

Mottled Skin
Born at term, a 15-day-old neonate presented with sepsis and mottling of the skin. The patient did not have any typical COVID-19 symptoms, such as diarrhea or cough, but tested positive for COVID-19.³⁰

Periorbital Dyschromia
Kalner and Vergilis³¹ reported 2 cases of periorbital dyschromia prior to any other COVID-19 infection symptoms. The discoloration improved with resolution of ensuing viral symptoms.³¹

Comment

Many dermatologic signs of COVID-19 have been identified. Their individual frequency and association with viral severity will become more apparent as more cases are reported. So far during this pandemic, common dermatologic manifestations have been polymorphic in clinical presentation.

Onset of Skin Manifestations
The timeline of skin signs and COVID-19 symptoms varies from the first reported sign to weeks after symptom resolution. In the Region of Murcia, Spain, Pérez-Suárez et al¹⁴ collected data on cutaneous signs of patients with COVID-19. Of the patients studied, 9 had tests confirming COVID-19 infection. Truncal urticaria, sacral ulcers, acrocyanosis, and erythema multiforme were all reported in patients more than 2 weeks after symptom onset. One case of tinea infection also was reported 4 days after fever and respiratory symptoms began.¹⁴

Presentation
Coronavirus disease 2019 has affected the skin of both the central thorax and peripheral locations. In a study of 72 patients with cutaneous signs of COVID-19 by Sachdeva et al,⁸ a truncal distribution was most common, but 14 patients reported acral site involvement. Sachdeva et al⁸ reported urticarial reactions in 7 of 72 patients with cutaneous signs. A painful acral cyanosis was seen in 11 of 72 patients. Livedo reticularis presented in 2 patients, and only 1 patient had petechiae. Cutaneous signs were the first indicators of viral infection in 9 of 72 patients; 52 patients presented with respiratory symptoms first. All of the reported cutaneous signs spontaneously resolved within 10 days.⁸

Recalcati³² reviewed 88 patients with COVID-19, and 18 had cutaneous signs at initial onset of viral infection or during hospitalization. The most common integumentary sign reported in this study was erythema, followed by diffuse urticaria, and then a vesicular eruption resembling varicella infection.³²

Some less common phenomena have been identified in patients with COVID-19, including androgenic alopecia, exaggerated herpes zoster and postherpetic neuralgia, mottled skin, and periorbital dyschromia. Being aware of these complications may help in early treatment, diagnosis, and even prevention of viral spread.

Pathogenesis of Skin Manifestations
Few breakthroughs have been made in understanding the pathogenesis of skin manifestations of SARS-CoV-2. Acral ischemia may be a manifestation of COVID-19’s association with hypercoagulation. Increasing fibrinogen and prothrombin times lead to disseminated intravascular coagulation and microthrombi. These tiny blood clots then lodge in blood vessels and cause acral cyanosis and subsequent gangrene.² The proposed mechanism behind this clinical manifestation in younger populations is the hypercoagulable state that COVID-19 creates. Conversely, acral erythema and chilblainlike lesions in older patients are thought to be from acral ischemia as a response to insufficient type 1 interferons. This pathophysiologic mechanism is indicative of a worse prognosis due to the large role that type 1 interferons play in antiviral responses. Coronavirus disease 2019 similarly triggers type 1 interferons; thus, their efficacy positively correlates with good disease prognosis.³

Similarly, the pathogenesis for livedo reticularis in patients with COVID-19 can only be hypothesized. Infected patients are in a hypercoagulable state, and in these cases, it was uncertain whether this was due to a disseminated intravascular coagulation, cold agglutinins, cryofibrinogens, or lupus anticoagulant.¹⁶

Nonetheless, it can be difficult to separate the primary event between vasculopathy or vasculitis in larger vessel pathology specimens. Some of the studies’ pathology reports discuss a granulocytic infiltrate and red blood cell extravasation, which represent small vessel vasculitis. However, the gangrene and necrosing livedo represent vasculopathy events. A final conclusion about the pathogenesis cannot be made without further clinical and histopathologic evaluation.

Histopathology
Biopsy specimens of reported morbilliform eruptions have demonstrated thrombosed vessels with evidence of necrosis and granulocytic infiltrate.²⁵ Another biopsy specimen of a widespread erythematous exanthem demonstrated extravasated red blood cells and vessel wall damage similar to thrombophilic arteritis. Other reports of histopathology showed necrotic keratinocytes and lymphocytic satellitosis at the dermoepidermal junction, resembling Grover disease. These cases demonstrating necrosis suggest a strong cytokine reaction from the virus.²⁵ A concern with these biopsy findings is that morbilliform eruptions generally show dilated vessels with lymphocytes, and these biopsy findings are consistent with a cutaneous small vessel vasculitis. Additionally, histopathologic evaluation of purpuric eruptions has shown erythrocyte extravasation and granulocytic infiltrate indicative of a cutaneous small vessel vasculitis.

Although most reported cases of cutaneous signs of COVID-19 do not have histopathologic reports, Yao et al³³ conducted a dermatopathologic study that investigated the tissue in deceased patients who had COVID-19. This pathology showed hyaline thrombi within the small vessels of the skin, likely leading to the painful acral ischemia. Similarly, Yao et al³³ reported autopsies finding hyaline thrombi within the small vessels of the lungs. More research should be done to explore this pathogenesis as part of prognostic factors and virulence.

Conclusion

Cutaneous signs may be the first reported symptom of COVID-19 infection, and dermatologists should be prepared to identify them. This review may be used as a guide for physicians to quickly identify potential infection as well as further understand the pathogenesis related to COVID-19. Future research is necessary to determine the dermatologic pathogenesis, infectivity, and prevalence of cutaneous manifestations of COVID-19. It also will be important to explore if vasculopathic lesions predict more severe multisystem disease.

The pathogenesis of coronavirus disease 2019 (COVID-19), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not yet completely understood. Thus far, it is known to affect multiple organ systems, including gastrointestinal, neurological, and cardiovascular, with typical clinical symptoms of COVID-19 including fever, cough, myalgia, headache, anosmia, and diarrhea.¹ This multiorgan attack may be secondary to an exaggerated inflammatory reaction with vasculopathy and possibly a hypercoagulable state. Skin manifestations also are prevalent in COVID-19, and they often result in polymorphous presentations.² This article aims to summarize cutaneous clinical signs of COVID-19 so that dermatologists can promptly identify and manage COVID-19 and prevent its spread.

Methods

A PubMed search of articles indexed for MEDLINE was conducted on June 30, 2020. The literature included observational studies, case reports, and literature reviews from January 1, 2020, to June 30, 2020. Search terms included COVID-19, SARS-CoV-2, and coronavirus used in combination with cutaneous, skin, and dermatology. All of the resulting articles were then reviewed for relevance to the cutaneous manifestations of COVID-19. Only confirmed cases of COVID-19 infection were included in this review; suspected unconfirmed cases were excluded. Further exclusion criteria included articles that discussed dermatology in the time of COVID-19 that did not explicitly address its cutaneous manifestations. The remaining literature was evaluated to provide dermatologists and patients with a concise resource for the cutaneous signs and symptoms of COVID-19. Data extracted from the literature included geographic region, number of patients with skin findings, status of COVID-19 infection and timeline, and cutaneous signs. If a cutaneous sign was not given a clear diagnosis in the literature, the senior authors (A.L. and J.J.) assigned it to its most similar classification to aid in ease of understanding and clarity for the readers.

Results

A search of the key terms resulted in 75 articles published in the specified date range. After excluding overtly irrelevant articles and dermatologic conditions in the time of COVID-19 without confirmed SARS-CoV-2 infection, 25 articles ultimately met inclusion criteria. Relevant references from the articles also were explored for cutaneous dermatologic manifestations of COVID-19. Cutaneous manifestations that were repeatedly reported included chilblainlike lesions; acrocyanosis; urticaria; pityriasis rosea–like cutaneous eruption; erythema multiforme–like, vesiculopapular, and morbilliform eruptions; petechiae; livedo reticularis; and purpuric livedo reticularis (dermatologists may label this stellate purpura). Fewer but nonetheless notable cases of androgenic alopecia, periorbital dyschromia, and herpes zoster exacerbations also were documented. The Table summarizes the reported integumentary findings. The eTable groups the common findings and describes patient age, time to onset of cutaneous sign, and any prognostic significance as seen in the literature.

Chilblainlike Lesions and Acrocyanosis
Chilblainlike lesions are edematous eruptions of the fingers and toes. They usually do not scar and are described as erythematous to violaceous papules and macules with possible bullae on the digits. Skin biopsies demonstrate a histopathologic pattern of vacuolar interface dermatitis with necrotic keratinocytes and a thickened basement membrane. Lymphocytic infiltrate presents in a perieccrine distribution, occasionally with plasma cells. The dermatopathologic findings mimic those of chilblain lupus but lack dermal edema.³

These eruptions have been reported in cases of COVID-19 that more frequently affect children and young adults. They usually resolve over the course of viral infection, averaging within 14 days. Chilblainlike eruptions often are associated with pruritus or pain. They commonly are asymmetrical and appear more often on the toes than the fingers.⁴ In cases of COVID-19 that lack systemic symptoms, chilblainlike lesions have been seen on the dorsal fingers as the first presenting sign of infection.⁵

Acral erythema and chilblainlike lesions frequently have been associated with milder infection. Another positive prognostic indicator is the manifestation of these signs in younger individuals.³

Morbilliform Exanthem
The morbilliform exanthem associated with COVID-19 also typically presents in patients with milder disease. It often affects the buttocks, lower abdomen, and thighs, but spares the palms, soles, and mucosae.⁴ This skin sign, which may start out as a generalized morbilliform exanthem, has been seen to morph into macular hemorrhagic purpura on the legs. These cutaneous lesions typically spontaneously resolve.⁸

In a case report by Najarian,⁶ a morbilliform exanthem was seen on the legs, arms, and trunk of a patient who was otherwise asymptomatic but tested positive for COVID-19. The morbilliform exanthem then became confluent on the trunk. Notably, the patient reported pain of the hands and feet.⁶

Another case report described a patient with edematous annular plaques on the palms, neck, and upper extremities who presented solely with fever.⁷ The biopsy specimen was nonspecific but indicated a viral exanthem. Histopathology showed perivascular lymphocytic infiltrate, dermal edema and vacuoles, spongiosis, dyskeratotic basilar keratinocytes, and few neutrophils without eosinophils.⁷

Eczematous Eruption
A confluent eczematous eruption in the flexural areas, the antecubital fossae, and axillary folds has been found in COVID-19 patients.^21,22 An elderly patient with severe COVID-19 developed a squamous erythematous periumbilical patch 1 day after hospital admission. The cutaneous eruption rapidly progressed to digitate scaly plaques on the trunk, thighs, and flank. A biopsy specimen showed epidermal spongiosis, vesicles containing lymphocytes, and Langerhans cells. The upper dermis demonstrated a lymphohistiocytic infiltrate.²³

Pityriasis Rosea–Like Eruption
In Iran, a COVID-19–infected patient developed an erythematous papulosquamous eruption with a herald patch and trailing scales 3 days after viral symptoms, resembling that of pityriasis rosea.²⁴ Nests of Langerhans cells within the epidermis are seen in many viral exanthems, including cases of COVID-19 and pityriasis rosea.²⁵

Urticaria
According to a number of case reports, urticarial lesions have been the first presenting sign of COVID-19 infection, most resolving with antihistamines.^10,11 Some patients with more severe symptoms have had widespread urticaria. An urticarial exanthem appearing on the bilateral thighs and buttocks may be the initial sign of infection.^12,15 Pruritic erythematous plaques over the face and acral areas is another initial sign. Interestingly, pediatric patients have reported nonpruritic urticaria.⁹

Urticaria also has been seen as a late dermatologic sign of viral infection. After battling relentless viral infection for 1 month, a pruritic, confluent, ill-defined eruption appeared along a patient’s trunk, back, and proximal extremities. Histopathologic examination concluded a perivascular lymphocytic infiltrate and dilated vessels in the dermis. The urticaria resolved a week later, and the patient’s nasopharyngeal swab finally came back negative.¹³

Vesiculopapular Eruption
Vesicles mimicking those of chickenpox have been reported. A study of 375 confirmed cases of COVID-19 by Galván Casas et al¹² showed a 9% incidence of this vesicular eruption. A study by Sachdeva et al⁸ revealed vesicular eruptions in 25 of 72 patients. Pruritic papules and vesicles may resemble Grover disease. This cutaneous sign may be seen in the submammary folds, on the hips, or diffusely over the body.

Erythema Multiforme–Like Eruption
Targetoid lesions similar to those of erythema multiforme erupted in 2 of 27 patients with mild COVID-19 infection in a review by Wollina et al.⁴ In a study of 4 patients with erythema multiforme–like eruptions after COVID-19 symptoms resolved, 3 had palatal petechiae. Two of 4 patients had pseudovesicles in the center of the erythematous targetoid patches.²⁶ Targetoid lesions on the extremities have been reported in pediatric patients with COVID-19 infections. These patients often present without any typical viral symptoms but rather just a febrile exanthem or exanthem alone. Thus, to minimize spread of the virus, it is vital to recognize COVID-19 infection early in patients with a viral exanthem during the time of high COVID-19 incidence.⁴

Livedo Reticularis
In the United States, a case series reported 2 patients with transient livedo reticularis throughout the course of COVID-19 infection. The cutaneous eruption resembled erythema ab igne, but there was no history of exposure to heat.¹⁶

Stellate Purpura
In severe COVID-19 infection, a reticulated nonblanching purpura on the buttocks has been reported to demonstrate pauci-inflammatory vascular thrombosis, complement membrane attack complex deposition, and endothelial injury on dermatopathology. Stellate purpura on palmoplantar surfaces also has shown arterial thrombosis in the deep dermis due to complement deposition.¹⁷

Petechiae and Purpura
A morbilliform exanthem may develop into significant petechiae in the popliteal fossae, buttocks, and thighs. A punch biopsy specimen demonstrates a perivascular lymphocytic infiltrate with erythrocyte extravasation and papillary dermal edema with dyskeratotic cells.¹⁸ Purpura of the lower extremities may develop, with histopathology showing fibrinoid necrosis of small vessel walls, neutrophilic infiltrate with karyorrhexis, and granular complement deposition.¹⁹

In Thailand, a patient was misdiagnosed with dengue after presenting with petechiae and low platelet count.²⁰ Further progression of the viral illness resulted in respiratory symptoms. Subsequently, the patient tested positive for COVID-19. This case demonstrates that cutaneous signs of many sorts may be the first presenting signs of COVID-19, even prior to febrile symptoms.²⁰

Androgenic Alopecia
Studies have shown that androgens are related in the pathogenesis of COVID-19. Coronavirus disease 2019 uses a cellular co-receptor, TMPRSS2, which is androgen regulated.²⁷ In a study of 41 males with COVID-19, 29 had androgenic alopecia. However, this is only a correlation, and causation cannot be concluded here. It cannot be determined from this study whether androgenic alopecia is a risk factor, result of COVID-19, or confounder.²⁸

Exaggerated Herpes Zoster
Shors²⁹ reported a herpes zoster eruption in a patient who had symptoms of COVID-19 for 1 week. Further testing confirmed COVID-19 infection, and despite prompt treatment with valacyclovir, the eruption was slow to resolve. The patient then experienced severe postherpetic neuralgia for more than 4 weeks, even with treatment with gabapentin and lidocaine. It is hypothesized that because of the major inflammatory response caused by COVID-19, an exaggerated inflammation occurred in the dorsal root ganglion, resulting in relentless herpes zoster infection.²⁹

Mottled Skin
Born at term, a 15-day-old neonate presented with sepsis and mottling of the skin. The patient did not have any typical COVID-19 symptoms, such as diarrhea or cough, but tested positive for COVID-19.³⁰

Periorbital Dyschromia
Kalner and Vergilis³¹ reported 2 cases of periorbital dyschromia prior to any other COVID-19 infection symptoms. The discoloration improved with resolution of ensuing viral symptoms.³¹

Comment

Many dermatologic signs of COVID-19 have been identified. Their individual frequency and association with viral severity will become more apparent as more cases are reported. So far during this pandemic, common dermatologic manifestations have been polymorphic in clinical presentation.

Onset of Skin Manifestations
The timeline of skin signs and COVID-19 symptoms varies from the first reported sign to weeks after symptom resolution. In the Region of Murcia, Spain, Pérez-Suárez et al¹⁴ collected data on cutaneous signs of patients with COVID-19. Of the patients studied, 9 had tests confirming COVID-19 infection. Truncal urticaria, sacral ulcers, acrocyanosis, and erythema multiforme were all reported in patients more than 2 weeks after symptom onset. One case of tinea infection also was reported 4 days after fever and respiratory symptoms began.¹⁴

Presentation
Coronavirus disease 2019 has affected the skin of both the central thorax and peripheral locations. In a study of 72 patients with cutaneous signs of COVID-19 by Sachdeva et al,⁸ a truncal distribution was most common, but 14 patients reported acral site involvement. Sachdeva et al⁸ reported urticarial reactions in 7 of 72 patients with cutaneous signs. A painful acral cyanosis was seen in 11 of 72 patients. Livedo reticularis presented in 2 patients, and only 1 patient had petechiae. Cutaneous signs were the first indicators of viral infection in 9 of 72 patients; 52 patients presented with respiratory symptoms first. All of the reported cutaneous signs spontaneously resolved within 10 days.⁸

Recalcati³² reviewed 88 patients with COVID-19, and 18 had cutaneous signs at initial onset of viral infection or during hospitalization. The most common integumentary sign reported in this study was erythema, followed by diffuse urticaria, and then a vesicular eruption resembling varicella infection.³²

Some less common phenomena have been identified in patients with COVID-19, including androgenic alopecia, exaggerated herpes zoster and postherpetic neuralgia, mottled skin, and periorbital dyschromia. Being aware of these complications may help in early treatment, diagnosis, and even prevention of viral spread.

Pathogenesis of Skin Manifestations
Few breakthroughs have been made in understanding the pathogenesis of skin manifestations of SARS-CoV-2. Acral ischemia may be a manifestation of COVID-19’s association with hypercoagulation. Increasing fibrinogen and prothrombin times lead to disseminated intravascular coagulation and microthrombi. These tiny blood clots then lodge in blood vessels and cause acral cyanosis and subsequent gangrene.² The proposed mechanism behind this clinical manifestation in younger populations is the hypercoagulable state that COVID-19 creates. Conversely, acral erythema and chilblainlike lesions in older patients are thought to be from acral ischemia as a response to insufficient type 1 interferons. This pathophysiologic mechanism is indicative of a worse prognosis due to the large role that type 1 interferons play in antiviral responses. Coronavirus disease 2019 similarly triggers type 1 interferons; thus, their efficacy positively correlates with good disease prognosis.³

Similarly, the pathogenesis for livedo reticularis in patients with COVID-19 can only be hypothesized. Infected patients are in a hypercoagulable state, and in these cases, it was uncertain whether this was due to a disseminated intravascular coagulation, cold agglutinins, cryofibrinogens, or lupus anticoagulant.¹⁶

Nonetheless, it can be difficult to separate the primary event between vasculopathy or vasculitis in larger vessel pathology specimens. Some of the studies’ pathology reports discuss a granulocytic infiltrate and red blood cell extravasation, which represent small vessel vasculitis. However, the gangrene and necrosing livedo represent vasculopathy events. A final conclusion about the pathogenesis cannot be made without further clinical and histopathologic evaluation.

Histopathology
Biopsy specimens of reported morbilliform eruptions have demonstrated thrombosed vessels with evidence of necrosis and granulocytic infiltrate.²⁵ Another biopsy specimen of a widespread erythematous exanthem demonstrated extravasated red blood cells and vessel wall damage similar to thrombophilic arteritis. Other reports of histopathology showed necrotic keratinocytes and lymphocytic satellitosis at the dermoepidermal junction, resembling Grover disease. These cases demonstrating necrosis suggest a strong cytokine reaction from the virus.²⁵ A concern with these biopsy findings is that morbilliform eruptions generally show dilated vessels with lymphocytes, and these biopsy findings are consistent with a cutaneous small vessel vasculitis. Additionally, histopathologic evaluation of purpuric eruptions has shown erythrocyte extravasation and granulocytic infiltrate indicative of a cutaneous small vessel vasculitis.

Although most reported cases of cutaneous signs of COVID-19 do not have histopathologic reports, Yao et al³³ conducted a dermatopathologic study that investigated the tissue in deceased patients who had COVID-19. This pathology showed hyaline thrombi within the small vessels of the skin, likely leading to the painful acral ischemia. Similarly, Yao et al³³ reported autopsies finding hyaline thrombi within the small vessels of the lungs. More research should be done to explore this pathogenesis as part of prognostic factors and virulence.

Conclusion

Cutaneous signs may be the first reported symptom of COVID-19 infection, and dermatologists should be prepared to identify them. This review may be used as a guide for physicians to quickly identify potential infection as well as further understand the pathogenesis related to COVID-19. Future research is necessary to determine the dermatologic pathogenesis, infectivity, and prevalence of cutaneous manifestations of COVID-19. It also will be important to explore if vasculopathic lesions predict more severe multisystem disease.

Psoriasis is a chronic relapsing skin condition characterized by keratinocyte hyperproliferation and a chronic inflammatory cascade. Therefore, controlling inflammatory responses with systemic medications is beneficial in managing psoriatic lesions and their accompanying symptoms, especially in disease inadequately controlled by topicals. Ease of drug administration and treatment availability are benefits that systemic nonbiologic therapies may have over biologic therapies.

In 2020, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) published guidelines for managing psoriasis in adults with systemic nonbiologic therapies.¹ Dosing, efficacy, toxicity, drug-related interactions, and contraindications are addressed alongside evidence-based treatment recommendations. This review addresses current recommendations for systemic nonbiologics in psoriasis with a focus on the treatments approved by the US Food and Drug Administration (FDA): acitretin, apremilast, cyclosporine, and methotrexate (eTable). Fumaric acid esters and tofacitinib are FDA approved for psoriatic arthritis but not for plaque psoriasis. Additional long-term safety analyses of tofacitinib for plaque psoriasis were requested by the FDA. Dimethyl fumarate is approved by the European Medicines Agency for treatment of psoriasis and is among the first-line systemic treatments used in Germany.²

Selecting a Systemic Nonbiologic Agent

Methotrexate and apremilast have a strength level A recommendation for treating moderate to severe psoriasis in adults. However, methotrexate is less effective than biologic agents, including adalimumab and infliximab, for cutaneous psoriasis. Methotrexate is believed to improve psoriasis because of its direct immunosuppressive effect and inhibition of lymphoid cell proliferation. It typically is administered orally but can be administered subcutaneously for decreased gastrointestinal (GI) adverse effects. Compliance with close laboratory monitoring and lifestyle modifications, such as contraceptive use (because of teratogenicity) and alcohol cessation (because of the risk of liver damage) are essential in patients using methotrexate.

Apremilast, the most recently FDA-approved oral systemic medication for psoriasis, inhibits phosphodiesterase 4, subsequently decreasing inflammatory responses involving helper T cells T_H1 and T_H17 as well as type 1 interferon pathways. Apremilast is particularly effective in treating psoriasis with scalp and palmoplantar involvement.³ Additionally, it has an encouraging safety profile and is favorable in patients with multiple comorbidities.

Among the 4 oral agents, cyclosporine has the quickest onset of effect and has a strength level A recommendation for treating severe and recalcitrant psoriasis. Because of its high-risk profile, it is recommended for short periods of time, acute flares, or during transitions to safer long-term treatment. Patients with multiple comorbidities should avoid cyclosporine as a treatment option.

Acitretin, an FDA-approved oral retinoid, is an optimal treatment option for immunosuppressed patients or patients with HIV on antiretroviral therapy because it is not immunosuppressive.⁴ Unlike cyclosporine, acitretin is less helpful for acute flares because it takes 3 to 6 months to reach peak therapeutic response for treating plaque psoriasis. Similar to cyclosporine, acitretin can be recommended for severe psoriatic variants of erythrodermic, generalized pustular, and palmoplantar psoriasis. Acitretin has been reported to be more effective and have a more rapid onset of action in erythrodermic and pustular psoriasis than in plaque psoriasis.⁵

Patient Comorbidities

Psoriatic arthritis (PsA) is a common comorbidity that affects treatment choice. Patients with coexisting PsA could be treated with apremilast, as it is approved for both psoriasis and PsA. In a phase 3 randomized, controlled trial, American College of Rheumatology (ACR) 20 response at weeks 16 and 52 was achieved by significantly more patients on apremilast at 20 mg twice daily (BID)(P=.0166) or 30 mg BID (P=.0001) than placebo.⁶ Although not FDA approved for PsA, methotrexate has been shown to improve concomitant PsA of the peripheral joints in patients with psoriasis. Furthermore, a trial of methotrexate has shown considerable improvements in PsA symptoms in patients with psoriasis—a 62.7% decrease in proportion of patients with dactylitis, 25.7% decrease in enthesitis, and improvements in ACR outcomes (ACR20 in 40.8%, ACR50 in 18.8%, and ACR70 in 8.6%, with 22.4% achieving minimal disease activity).⁷

Prior to starting a systemic medication for psoriasis, it is necessary to discuss effects on pregnancy and fertility. Pregnancy is an absolute contraindication for methotrexate and acitretin use because of the drugs’ teratogenicity. Fetal death and fetal abnormalities have been reported with methotrexate use in pregnant women.⁸ Bone, central nervous system, auditory, ocular, and cardiovascular fetal abnormalities have been reported with maternal acitretin use.⁹ Breastfeeding also is an absolute contraindication for methotrexate use, as methotrexate passes into breastmilk in small quantities. Patients taking acitretin also are strongly discouraged from nursing because of the long half-life (168 days) of etretinate, a reverse metabolism product of acitretin that is increased in the presence of alcohol. Women should wait 3 months after discontinuing methotrexate for complete drug clearance before conceiving compared to 3 years in women who have discontinued acitretin.^8,10 Men also are recommended to wait 3 months after discontinuing methotrexate before attempting to conceive, as its effect on male spermatogenesis and teratogenicity is unclear. Acitretin has no documented teratogenic effect in men. For women planning to become pregnant, apremilast and cyclosporine can be continued throughout pregnancy on an individual basis. The benefit of apremilast should be weighed against its potential risk to the fetus. There is no evidence of teratogenicity of apremilast at doses of 20 mg/kg daily.¹¹ Current research regarding cyclosporine use in pregnancy only exists in transplant patients and has revealed higher rates of prematurity and lower birth weight without teratogenic effects.^10,12 The risks and benefits of continuing cyclosporine while nursing should be evaluated, as cyclosporine (and ethanol-methanol components used in some formulations) is detectable in breast milk.

Drug Contraindications

Hypersensitivity to a specific systemic nonbiologic medication is a contraindication to its use and is an absolute contraindication for methotrexate. Other absolute contraindications to methotrexate are pregnancy and nursing, alcoholism, alcoholic liver disease, chronic liver disease, immunodeficiency, and cytopenia. Contraindications to acitretin include pregnancy, severely impaired liver and kidney function, and chronic abnormally elevated lipid levels. There are no additional contraindications for apremilast, but patients must be informed of the risk for depression before initiating therapy. Cyclosporine is contraindicated in patients with prior psoralen plus UVA (PUVA) treatment or radiation therapy, abnormal renal function, uncontrolled hypertension, uncontrolled and active infections, and a history of systemic malignancy. Live vaccines should be avoided in patients on cyclosporine, and caution is advised when cyclosporine is prescribed for patients with poorly controlled diabetes.

Pretreatment Screening

Because of drug interactions, a detailed medication history is essential prior to starting any systemic medication for psoriasis. Apremilast and cyclosporine are metabolized by cytochrome P450 and therefore are more susceptible to drug-related interactions. Cyclosporine use can affect levels of other medications that are metabolized by cytochrome P450, such as statins, calcium channel blockers, and warfarin. Similarly, acitretin’s metabolism is affected by drugs that interfere with cytochrome P450. Additionally, screening laboratory tests are needed before initiating systemic nonbiologic agents for psoriasis, with the exception of apremilast.

Prior to initiating methotrexate treatment, patients may require tuberculosis (TB), hepatitis B, and hepatitis C screening tests, depending on their risk factors. A baseline liver fibrosis assessment is recommended because of the potential of hepatotoxicity in patients receiving methotrexate. Noninvasive serology tests utilized to evaluate the presence of pre-existing liver disease include Fibrosis-4, FibroMeter, FibroSure, and Hepascore. Patients with impaired renal function have an increased predisposition to methotrexate-induced hematologic toxicity. Thus, it is necessary to administer a test dose of methotrexate in these patients followed by a complete blood cell count (CBC) 5 to 7 days later. An unremarkable CBC after the test dose suggests the absence of myelosuppression, and methotrexate dosage can be increased weekly. Patients on methotrexate also must receive folate supplementation to reduce the risk for adverse effects during treatment.

Patients considering cyclosporine must undergo screening for family and personal history of renal disease. Prior to initiating treatment, patients require 2 blood pressure measurements, hepatitis screening, TB screening, urinalysis, serum creatinine (Cr), blood urea nitrogen (BUN), CBC, potassium and magnesium levels, uric acid levels, lipid profile, bilirubin, and liver function tests (LFTs). A pregnancy test also is warranted for women of childbearing potential (WOCP).

Patients receiving acitretin should receive screening laboratory tests consisting of fasting cholesterol and triglycerides, CBC, renal function tests, LFTs, and a pregnancy test, if applicable.

After baseline evaluations, the selected oral systemic can be initiated using specific dosing regimens to ensure optimal drug efficacy and reduce incidence of adverse effects (eTable).

Monitoring During Active Treatment

Physicians need to counsel patients on potential adverse effects of their medications. Because of its relatively safe profile among the systemic nonbiologic agents, apremilast requires the least monitoring during treatment. There is no required routine laboratory monitoring for patients using apremilast, though testing may be pursued at the clinician’s discretion. However, weight should be regularly measured in patients on apremilast. In a phase 3 clinical trial of patients with psoriasis, 12% of patients on apremilast experienced a 5% to 10% weight loss compared to 5% of patients on placebo.^11,13 Thus, it is recommended that physicians consider discontinuing apremilast in patients with a weight loss of more than 5% from baseline, especially if it may lead to other unfavorable health effects. Because depression is reported among 1% of patients on apremilast, close monitoring for new or worsening symptoms of depression should be performed during treatment.^11,13 To avoid common GI side effects, apremilast is initiated at 10 mg/d and is increased by 10 mg/d over the first 5 days to a final dose of 30 mg BID. Elderly patients in particular should be cautioned about the risk of dehydration associated with GI side effects. Patients with severe renal impairment (Cr clearance, <30 mL/min) should use apremilast at a dosage of 30 mg once daily.

For patients on methotrexate, laboratory monitoring is essential after each dose increase. It also is important for physicians to obtain regular blood work to assess for hematologic abnormalities and hepatoxicity. Patients with risk factors such as renal insufficiency, increased age, hypoalbuminemia, alcohol abuse and alcoholic liver disease, and methotrexate dosing errors, as well as those prone to drug-related interactions, must be monitored closely for pancytopenia.^14,15 The protocol for screening for methotrexate-induced hepatotoxicity during treatment depends on patient risk factors. Risk factors for hepatoxicity include history of or current alcohol abuse, abnormal LFTs, personal or family history of liver disease, diabetes, obesity, use of other hepatotoxic drugs, and hyperlipidemia.¹⁶ In patients without blood work abnormalities, CBC and LFTs can be performed every 3 to 6 months. Patients with abnormally elevated LFTs require repeat blood work every 2 to 4 weeks. Persistent elevations in LFTs require further evaluation by a GI specialist. After a cumulative dose of 3.5 to 4 g, patients should receive a GI referral and further studies (such as vibration-controlled transient elastography or liver biopsy) to assess for liver fibrosis. Patients with signs of stage 3 liver fibrosis are recommended to discontinue methotrexate and switch to another medication for psoriasis. For patients with impaired renal function, periodic BUN and Cr monitoring are needed. Common adverse effects of methotrexate include diarrhea, nausea, and anorexia, which can be mitigated by taking methotrexate with food or lowering the dosage.⁸ Patients on methotrexate should be monitored for rare but potential risks of infection and reactivation of latent TB, hepatitis, and lymphoma. To reduce the incidence of methotrexate toxicity from drug interactions, a review of current medications at each follow-up visit is recommended.

Nephrotoxicity and hypertension are the most common adverse effects of cyclosporine. It is important to monitor BUN and Cr biweekly for the initial 3 months, then at monthly intervals if there are no persistent abnormalities. Patients also must receive monthly CBC, potassium and magnesium levels, uric acid levels, lipid panel, serum bilirubin, and LFTs to monitor for adverse effects.¹⁷ Physicians should obtain regular pregnancy tests in WOCP. Weekly monitoring of early-morning blood pressure is recommended for patients on cyclosporine to detect early cyclosporine-induced nephrotoxicity. Hypertension on 2 separate occasions warrants a reduction in cyclosporine dosage or an addition of a calcium channel blocker for blood pressure control. Dose reduction also should be performed in patients with an increase in Cr above baseline greater than 25%.¹⁷ If Cr level is persistently elevated or if blood pressure does not normalize to lower than 140/90 after dose reduction, cyclosporine should be immediately discontinued. Patients on cyclosporine for more than a year warrant an annual estimation of glomerular filtration rate because of irreversible kidney damage associated with long-term use. A systematic review of patients treated with cyclosporine for more than 2 years found that at least 50% of patients experienced a 30% increase in Cr above baseline.¹⁸

Patients taking acitretin should be monitored for hyperlipidemia, the most common laboratory abnormality seen in 25% to 50% of patients.¹⁹ Fasting lipid panel and LFTs should be performed monthly for the initial 3 months on acitretin, then at 3-month intervals. Lifestyle changes should be encouraged to reduce hyperlipidemia, and fibrates may be given to treat elevated triglyceride levels, the most common type of hyperlipidemia seen with acitretin. Acitretin-induced toxic hepatitis is a rare occurrence that warrants immediate discontinuation of the medication.²⁰ Monthly pregnancy tests must be performed in WOCP.

Combination Therapy

For apremilast, there is anecdotal evidence supporting its use in conjunction with phototherapy or biologics in some cases, but no high-quality data.²¹ On the other hand, using combination therapy with other systemic therapies can reduce adverse effects and decrease the amount of medication needed to achieve psoriasis clearance. Methotrexate used with etanercept, for example, has been more effective than methotrexate monotherapy in treating psoriasis, which has been attributed to a methotrexate-mediated reduction in the production of antidrug antibodies.^22,23

Methotrexate, cyclosporine, and acitretin have synergistic effects when used with phototherapy. Narrowband UVB (NB-UVB) phototherapy combined with methotrexate is more effective in clearing psoriasis than methotrexate or NB-UVB phototherapy alone. Similarly, acitretin and PUVA combination therapy is more effective than acitretin or PUVA phototherapy alone. Combination regimens of acitretin and broadband UVB phototherapy, acitretin and NB-UVB phototherapy, and acitretin and PUVA phototherapy also have been more effective than individual modalities alone. Combination therapy reduces the cumulative doses of both therapies and reduces the frequency and duration of phototherapy needed for psoriatic clearance.²⁴ In acitretin combination therapy with UVB phototherapy, the recommended regimen is 2 weeks of acitretin monotherapy followed by UVB phototherapy. For patients with an inadequate response to UVB phototherapy, the UVB dose can be reduced by 30% to 50%, and acitretin 25 mg/d can be added to phototherapy treatment. Acitretin-UVB combination therapy has been shown to reduce the risk of UVB-induced erythema seen in UVB monotherapy. Similarly, the risk of squamous cell carcinoma is reduced in acitretin-PUVA combination therapy compared to PUVA monotherapy.²⁵

The timing of phototherapy in combination with systemic nonbiologic agents is critical. Phototherapy used simultaneously with cyclosporine is contraindicated owing to increased risk of photocarcinogenesis, whereas phototherapy used in sequence with cyclosporine is well tolerated and effective. Furthermore, cyclosporine 3 mg/kg/d for 4 weeks followed by a rapid cyclosporine taper and initiation of NB-UVB phototherapy demonstrated resolution of psoriasis with fewer NB-UVB treatments and less UVB exposure than NB-UVB therapy alone.²⁶

Final Thoughts

The FDA-approved systemic nonbiologic agents are accessible and effective treatment options for adults with widespread or inadequately controlled psoriasis. Selecting the ideal therapy requires careful consideration of medication toxicity, contraindications, monitoring requirements, and patient comorbidities. The AAD-NPF guidelines guide dermatologists in prescribing systemic nonbiologic treatments in adults with psoriasis. Utilizing these recommendations in combination with clinician judgment will help patients achieve safe and optimal psoriasis clearance.

Psoriasis is a chronic relapsing skin condition characterized by keratinocyte hyperproliferation and a chronic inflammatory cascade. Therefore, controlling inflammatory responses with systemic medications is beneficial in managing psoriatic lesions and their accompanying symptoms, especially in disease inadequately controlled by topicals. Ease of drug administration and treatment availability are benefits that systemic nonbiologic therapies may have over biologic therapies.

In 2020, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) published guidelines for managing psoriasis in adults with systemic nonbiologic therapies.¹ Dosing, efficacy, toxicity, drug-related interactions, and contraindications are addressed alongside evidence-based treatment recommendations. This review addresses current recommendations for systemic nonbiologics in psoriasis with a focus on the treatments approved by the US Food and Drug Administration (FDA): acitretin, apremilast, cyclosporine, and methotrexate (eTable). Fumaric acid esters and tofacitinib are FDA approved for psoriatic arthritis but not for plaque psoriasis. Additional long-term safety analyses of tofacitinib for plaque psoriasis were requested by the FDA. Dimethyl fumarate is approved by the European Medicines Agency for treatment of psoriasis and is among the first-line systemic treatments used in Germany.²

Selecting a Systemic Nonbiologic Agent

Methotrexate and apremilast have a strength level A recommendation for treating moderate to severe psoriasis in adults. However, methotrexate is less effective than biologic agents, including adalimumab and infliximab, for cutaneous psoriasis. Methotrexate is believed to improve psoriasis because of its direct immunosuppressive effect and inhibition of lymphoid cell proliferation. It typically is administered orally but can be administered subcutaneously for decreased gastrointestinal (GI) adverse effects. Compliance with close laboratory monitoring and lifestyle modifications, such as contraceptive use (because of teratogenicity) and alcohol cessation (because of the risk of liver damage) are essential in patients using methotrexate.

Apremilast, the most recently FDA-approved oral systemic medication for psoriasis, inhibits phosphodiesterase 4, subsequently decreasing inflammatory responses involving helper T cells T_H1 and T_H17 as well as type 1 interferon pathways. Apremilast is particularly effective in treating psoriasis with scalp and palmoplantar involvement.³ Additionally, it has an encouraging safety profile and is favorable in patients with multiple comorbidities.

Among the 4 oral agents, cyclosporine has the quickest onset of effect and has a strength level A recommendation for treating severe and recalcitrant psoriasis. Because of its high-risk profile, it is recommended for short periods of time, acute flares, or during transitions to safer long-term treatment. Patients with multiple comorbidities should avoid cyclosporine as a treatment option.

Acitretin, an FDA-approved oral retinoid, is an optimal treatment option for immunosuppressed patients or patients with HIV on antiretroviral therapy because it is not immunosuppressive.⁴ Unlike cyclosporine, acitretin is less helpful for acute flares because it takes 3 to 6 months to reach peak therapeutic response for treating plaque psoriasis. Similar to cyclosporine, acitretin can be recommended for severe psoriatic variants of erythrodermic, generalized pustular, and palmoplantar psoriasis. Acitretin has been reported to be more effective and have a more rapid onset of action in erythrodermic and pustular psoriasis than in plaque psoriasis.⁵

Patient Comorbidities

Psoriatic arthritis (PsA) is a common comorbidity that affects treatment choice. Patients with coexisting PsA could be treated with apremilast, as it is approved for both psoriasis and PsA. In a phase 3 randomized, controlled trial, American College of Rheumatology (ACR) 20 response at weeks 16 and 52 was achieved by significantly more patients on apremilast at 20 mg twice daily (BID)(P=.0166) or 30 mg BID (P=.0001) than placebo.⁶ Although not FDA approved for PsA, methotrexate has been shown to improve concomitant PsA of the peripheral joints in patients with psoriasis. Furthermore, a trial of methotrexate has shown considerable improvements in PsA symptoms in patients with psoriasis—a 62.7% decrease in proportion of patients with dactylitis, 25.7% decrease in enthesitis, and improvements in ACR outcomes (ACR20 in 40.8%, ACR50 in 18.8%, and ACR70 in 8.6%, with 22.4% achieving minimal disease activity).⁷

Prior to starting a systemic medication for psoriasis, it is necessary to discuss effects on pregnancy and fertility. Pregnancy is an absolute contraindication for methotrexate and acitretin use because of the drugs’ teratogenicity. Fetal death and fetal abnormalities have been reported with methotrexate use in pregnant women.⁸ Bone, central nervous system, auditory, ocular, and cardiovascular fetal abnormalities have been reported with maternal acitretin use.⁹ Breastfeeding also is an absolute contraindication for methotrexate use, as methotrexate passes into breastmilk in small quantities. Patients taking acitretin also are strongly discouraged from nursing because of the long half-life (168 days) of etretinate, a reverse metabolism product of acitretin that is increased in the presence of alcohol. Women should wait 3 months after discontinuing methotrexate for complete drug clearance before conceiving compared to 3 years in women who have discontinued acitretin.^8,10 Men also are recommended to wait 3 months after discontinuing methotrexate before attempting to conceive, as its effect on male spermatogenesis and teratogenicity is unclear. Acitretin has no documented teratogenic effect in men. For women planning to become pregnant, apremilast and cyclosporine can be continued throughout pregnancy on an individual basis. The benefit of apremilast should be weighed against its potential risk to the fetus. There is no evidence of teratogenicity of apremilast at doses of 20 mg/kg daily.¹¹ Current research regarding cyclosporine use in pregnancy only exists in transplant patients and has revealed higher rates of prematurity and lower birth weight without teratogenic effects.^10,12 The risks and benefits of continuing cyclosporine while nursing should be evaluated, as cyclosporine (and ethanol-methanol components used in some formulations) is detectable in breast milk.

Drug Contraindications

Hypersensitivity to a specific systemic nonbiologic medication is a contraindication to its use and is an absolute contraindication for methotrexate. Other absolute contraindications to methotrexate are pregnancy and nursing, alcoholism, alcoholic liver disease, chronic liver disease, immunodeficiency, and cytopenia. Contraindications to acitretin include pregnancy, severely impaired liver and kidney function, and chronic abnormally elevated lipid levels. There are no additional contraindications for apremilast, but patients must be informed of the risk for depression before initiating therapy. Cyclosporine is contraindicated in patients with prior psoralen plus UVA (PUVA) treatment or radiation therapy, abnormal renal function, uncontrolled hypertension, uncontrolled and active infections, and a history of systemic malignancy. Live vaccines should be avoided in patients on cyclosporine, and caution is advised when cyclosporine is prescribed for patients with poorly controlled diabetes.

Pretreatment Screening

Because of drug interactions, a detailed medication history is essential prior to starting any systemic medication for psoriasis. Apremilast and cyclosporine are metabolized by cytochrome P450 and therefore are more susceptible to drug-related interactions. Cyclosporine use can affect levels of other medications that are metabolized by cytochrome P450, such as statins, calcium channel blockers, and warfarin. Similarly, acitretin’s metabolism is affected by drugs that interfere with cytochrome P450. Additionally, screening laboratory tests are needed before initiating systemic nonbiologic agents for psoriasis, with the exception of apremilast.

Prior to initiating methotrexate treatment, patients may require tuberculosis (TB), hepatitis B, and hepatitis C screening tests, depending on their risk factors. A baseline liver fibrosis assessment is recommended because of the potential of hepatotoxicity in patients receiving methotrexate. Noninvasive serology tests utilized to evaluate the presence of pre-existing liver disease include Fibrosis-4, FibroMeter, FibroSure, and Hepascore. Patients with impaired renal function have an increased predisposition to methotrexate-induced hematologic toxicity. Thus, it is necessary to administer a test dose of methotrexate in these patients followed by a complete blood cell count (CBC) 5 to 7 days later. An unremarkable CBC after the test dose suggests the absence of myelosuppression, and methotrexate dosage can be increased weekly. Patients on methotrexate also must receive folate supplementation to reduce the risk for adverse effects during treatment.

Patients considering cyclosporine must undergo screening for family and personal history of renal disease. Prior to initiating treatment, patients require 2 blood pressure measurements, hepatitis screening, TB screening, urinalysis, serum creatinine (Cr), blood urea nitrogen (BUN), CBC, potassium and magnesium levels, uric acid levels, lipid profile, bilirubin, and liver function tests (LFTs). A pregnancy test also is warranted for women of childbearing potential (WOCP).

Patients receiving acitretin should receive screening laboratory tests consisting of fasting cholesterol and triglycerides, CBC, renal function tests, LFTs, and a pregnancy test, if applicable.

After baseline evaluations, the selected oral systemic can be initiated using specific dosing regimens to ensure optimal drug efficacy and reduce incidence of adverse effects (eTable).

Monitoring During Active Treatment

Physicians need to counsel patients on potential adverse effects of their medications. Because of its relatively safe profile among the systemic nonbiologic agents, apremilast requires the least monitoring during treatment. There is no required routine laboratory monitoring for patients using apremilast, though testing may be pursued at the clinician’s discretion. However, weight should be regularly measured in patients on apremilast. In a phase 3 clinical trial of patients with psoriasis, 12% of patients on apremilast experienced a 5% to 10% weight loss compared to 5% of patients on placebo.^11,13 Thus, it is recommended that physicians consider discontinuing apremilast in patients with a weight loss of more than 5% from baseline, especially if it may lead to other unfavorable health effects. Because depression is reported among 1% of patients on apremilast, close monitoring for new or worsening symptoms of depression should be performed during treatment.^11,13 To avoid common GI side effects, apremilast is initiated at 10 mg/d and is increased by 10 mg/d over the first 5 days to a final dose of 30 mg BID. Elderly patients in particular should be cautioned about the risk of dehydration associated with GI side effects. Patients with severe renal impairment (Cr clearance, <30 mL/min) should use apremilast at a dosage of 30 mg once daily.

For patients on methotrexate, laboratory monitoring is essential after each dose increase. It also is important for physicians to obtain regular blood work to assess for hematologic abnormalities and hepatoxicity. Patients with risk factors such as renal insufficiency, increased age, hypoalbuminemia, alcohol abuse and alcoholic liver disease, and methotrexate dosing errors, as well as those prone to drug-related interactions, must be monitored closely for pancytopenia.^14,15 The protocol for screening for methotrexate-induced hepatotoxicity during treatment depends on patient risk factors. Risk factors for hepatoxicity include history of or current alcohol abuse, abnormal LFTs, personal or family history of liver disease, diabetes, obesity, use of other hepatotoxic drugs, and hyperlipidemia.¹⁶ In patients without blood work abnormalities, CBC and LFTs can be performed every 3 to 6 months. Patients with abnormally elevated LFTs require repeat blood work every 2 to 4 weeks. Persistent elevations in LFTs require further evaluation by a GI specialist. After a cumulative dose of 3.5 to 4 g, patients should receive a GI referral and further studies (such as vibration-controlled transient elastography or liver biopsy) to assess for liver fibrosis. Patients with signs of stage 3 liver fibrosis are recommended to discontinue methotrexate and switch to another medication for psoriasis. For patients with impaired renal function, periodic BUN and Cr monitoring are needed. Common adverse effects of methotrexate include diarrhea, nausea, and anorexia, which can be mitigated by taking methotrexate with food or lowering the dosage.⁸ Patients on methotrexate should be monitored for rare but potential risks of infection and reactivation of latent TB, hepatitis, and lymphoma. To reduce the incidence of methotrexate toxicity from drug interactions, a review of current medications at each follow-up visit is recommended.

Nephrotoxicity and hypertension are the most common adverse effects of cyclosporine. It is important to monitor BUN and Cr biweekly for the initial 3 months, then at monthly intervals if there are no persistent abnormalities. Patients also must receive monthly CBC, potassium and magnesium levels, uric acid levels, lipid panel, serum bilirubin, and LFTs to monitor for adverse effects.¹⁷ Physicians should obtain regular pregnancy tests in WOCP. Weekly monitoring of early-morning blood pressure is recommended for patients on cyclosporine to detect early cyclosporine-induced nephrotoxicity. Hypertension on 2 separate occasions warrants a reduction in cyclosporine dosage or an addition of a calcium channel blocker for blood pressure control. Dose reduction also should be performed in patients with an increase in Cr above baseline greater than 25%.¹⁷ If Cr level is persistently elevated or if blood pressure does not normalize to lower than 140/90 after dose reduction, cyclosporine should be immediately discontinued. Patients on cyclosporine for more than a year warrant an annual estimation of glomerular filtration rate because of irreversible kidney damage associated with long-term use. A systematic review of patients treated with cyclosporine for more than 2 years found that at least 50% of patients experienced a 30% increase in Cr above baseline.¹⁸

Patients taking acitretin should be monitored for hyperlipidemia, the most common laboratory abnormality seen in 25% to 50% of patients.¹⁹ Fasting lipid panel and LFTs should be performed monthly for the initial 3 months on acitretin, then at 3-month intervals. Lifestyle changes should be encouraged to reduce hyperlipidemia, and fibrates may be given to treat elevated triglyceride levels, the most common type of hyperlipidemia seen with acitretin. Acitretin-induced toxic hepatitis is a rare occurrence that warrants immediate discontinuation of the medication.²⁰ Monthly pregnancy tests must be performed in WOCP.

Combination Therapy

For apremilast, there is anecdotal evidence supporting its use in conjunction with phototherapy or biologics in some cases, but no high-quality data.²¹ On the other hand, using combination therapy with other systemic therapies can reduce adverse effects and decrease the amount of medication needed to achieve psoriasis clearance. Methotrexate used with etanercept, for example, has been more effective than methotrexate monotherapy in treating psoriasis, which has been attributed to a methotrexate-mediated reduction in the production of antidrug antibodies.^22,23

Methotrexate, cyclosporine, and acitretin have synergistic effects when used with phototherapy. Narrowband UVB (NB-UVB) phototherapy combined with methotrexate is more effective in clearing psoriasis than methotrexate or NB-UVB phototherapy alone. Similarly, acitretin and PUVA combination therapy is more effective than acitretin or PUVA phototherapy alone. Combination regimens of acitretin and broadband UVB phototherapy, acitretin and NB-UVB phototherapy, and acitretin and PUVA phototherapy also have been more effective than individual modalities alone. Combination therapy reduces the cumulative doses of both therapies and reduces the frequency and duration of phototherapy needed for psoriatic clearance.²⁴ In acitretin combination therapy with UVB phototherapy, the recommended regimen is 2 weeks of acitretin monotherapy followed by UVB phototherapy. For patients with an inadequate response to UVB phototherapy, the UVB dose can be reduced by 30% to 50%, and acitretin 25 mg/d can be added to phototherapy treatment. Acitretin-UVB combination therapy has been shown to reduce the risk of UVB-induced erythema seen in UVB monotherapy. Similarly, the risk of squamous cell carcinoma is reduced in acitretin-PUVA combination therapy compared to PUVA monotherapy.²⁵

The timing of phototherapy in combination with systemic nonbiologic agents is critical. Phototherapy used simultaneously with cyclosporine is contraindicated owing to increased risk of photocarcinogenesis, whereas phototherapy used in sequence with cyclosporine is well tolerated and effective. Furthermore, cyclosporine 3 mg/kg/d for 4 weeks followed by a rapid cyclosporine taper and initiation of NB-UVB phototherapy demonstrated resolution of psoriasis with fewer NB-UVB treatments and less UVB exposure than NB-UVB therapy alone.²⁶

Final Thoughts

The FDA-approved systemic nonbiologic agents are accessible and effective treatment options for adults with widespread or inadequately controlled psoriasis. Selecting the ideal therapy requires careful consideration of medication toxicity, contraindications, monitoring requirements, and patient comorbidities. The AAD-NPF guidelines guide dermatologists in prescribing systemic nonbiologic treatments in adults with psoriasis. Utilizing these recommendations in combination with clinician judgment will help patients achieve safe and optimal psoriasis clearance.

Psoriasis is a chronic relapsing skin condition characterized by keratinocyte hyperproliferation and a chronic inflammatory cascade. Therefore, controlling inflammatory responses with systemic medications is beneficial in managing psoriatic lesions and their accompanying symptoms, especially in disease inadequately controlled by topicals. Ease of drug administration and treatment availability are benefits that systemic nonbiologic therapies may have over biologic therapies.

In 2020, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) published guidelines for managing psoriasis in adults with systemic nonbiologic therapies.¹ Dosing, efficacy, toxicity, drug-related interactions, and contraindications are addressed alongside evidence-based treatment recommendations. This review addresses current recommendations for systemic nonbiologics in psoriasis with a focus on the treatments approved by the US Food and Drug Administration (FDA): acitretin, apremilast, cyclosporine, and methotrexate (eTable). Fumaric acid esters and tofacitinib are FDA approved for psoriatic arthritis but not for plaque psoriasis. Additional long-term safety analyses of tofacitinib for plaque psoriasis were requested by the FDA. Dimethyl fumarate is approved by the European Medicines Agency for treatment of psoriasis and is among the first-line systemic treatments used in Germany.²

Selecting a Systemic Nonbiologic Agent

Methotrexate and apremilast have a strength level A recommendation for treating moderate to severe psoriasis in adults. However, methotrexate is less effective than biologic agents, including adalimumab and infliximab, for cutaneous psoriasis. Methotrexate is believed to improve psoriasis because of its direct immunosuppressive effect and inhibition of lymphoid cell proliferation. It typically is administered orally but can be administered subcutaneously for decreased gastrointestinal (GI) adverse effects. Compliance with close laboratory monitoring and lifestyle modifications, such as contraceptive use (because of teratogenicity) and alcohol cessation (because of the risk of liver damage) are essential in patients using methotrexate.

Apremilast, the most recently FDA-approved oral systemic medication for psoriasis, inhibits phosphodiesterase 4, subsequently decreasing inflammatory responses involving helper T cells T_H1 and T_H17 as well as type 1 interferon pathways. Apremilast is particularly effective in treating psoriasis with scalp and palmoplantar involvement.³ Additionally, it has an encouraging safety profile and is favorable in patients with multiple comorbidities.

Among the 4 oral agents, cyclosporine has the quickest onset of effect and has a strength level A recommendation for treating severe and recalcitrant psoriasis. Because of its high-risk profile, it is recommended for short periods of time, acute flares, or during transitions to safer long-term treatment. Patients with multiple comorbidities should avoid cyclosporine as a treatment option.

Acitretin, an FDA-approved oral retinoid, is an optimal treatment option for immunosuppressed patients or patients with HIV on antiretroviral therapy because it is not immunosuppressive.⁴ Unlike cyclosporine, acitretin is less helpful for acute flares because it takes 3 to 6 months to reach peak therapeutic response for treating plaque psoriasis. Similar to cyclosporine, acitretin can be recommended for severe psoriatic variants of erythrodermic, generalized pustular, and palmoplantar psoriasis. Acitretin has been reported to be more effective and have a more rapid onset of action in erythrodermic and pustular psoriasis than in plaque psoriasis.⁵

Patient Comorbidities

Psoriatic arthritis (PsA) is a common comorbidity that affects treatment choice. Patients with coexisting PsA could be treated with apremilast, as it is approved for both psoriasis and PsA. In a phase 3 randomized, controlled trial, American College of Rheumatology (ACR) 20 response at weeks 16 and 52 was achieved by significantly more patients on apremilast at 20 mg twice daily (BID)(P=.0166) or 30 mg BID (P=.0001) than placebo.⁶ Although not FDA approved for PsA, methotrexate has been shown to improve concomitant PsA of the peripheral joints in patients with psoriasis. Furthermore, a trial of methotrexate has shown considerable improvements in PsA symptoms in patients with psoriasis—a 62.7% decrease in proportion of patients with dactylitis, 25.7% decrease in enthesitis, and improvements in ACR outcomes (ACR20 in 40.8%, ACR50 in 18.8%, and ACR70 in 8.6%, with 22.4% achieving minimal disease activity).⁷

Prior to starting a systemic medication for psoriasis, it is necessary to discuss effects on pregnancy and fertility. Pregnancy is an absolute contraindication for methotrexate and acitretin use because of the drugs’ teratogenicity. Fetal death and fetal abnormalities have been reported with methotrexate use in pregnant women.⁸ Bone, central nervous system, auditory, ocular, and cardiovascular fetal abnormalities have been reported with maternal acitretin use.⁹ Breastfeeding also is an absolute contraindication for methotrexate use, as methotrexate passes into breastmilk in small quantities. Patients taking acitretin also are strongly discouraged from nursing because of the long half-life (168 days) of etretinate, a reverse metabolism product of acitretin that is increased in the presence of alcohol. Women should wait 3 months after discontinuing methotrexate for complete drug clearance before conceiving compared to 3 years in women who have discontinued acitretin.^8,10 Men also are recommended to wait 3 months after discontinuing methotrexate before attempting to conceive, as its effect on male spermatogenesis and teratogenicity is unclear. Acitretin has no documented teratogenic effect in men. For women planning to become pregnant, apremilast and cyclosporine can be continued throughout pregnancy on an individual basis. The benefit of apremilast should be weighed against its potential risk to the fetus. There is no evidence of teratogenicity of apremilast at doses of 20 mg/kg daily.¹¹ Current research regarding cyclosporine use in pregnancy only exists in transplant patients and has revealed higher rates of prematurity and lower birth weight without teratogenic effects.^10,12 The risks and benefits of continuing cyclosporine while nursing should be evaluated, as cyclosporine (and ethanol-methanol components used in some formulations) is detectable in breast milk.

Drug Contraindications

Hypersensitivity to a specific systemic nonbiologic medication is a contraindication to its use and is an absolute contraindication for methotrexate. Other absolute contraindications to methotrexate are pregnancy and nursing, alcoholism, alcoholic liver disease, chronic liver disease, immunodeficiency, and cytopenia. Contraindications to acitretin include pregnancy, severely impaired liver and kidney function, and chronic abnormally elevated lipid levels. There are no additional contraindications for apremilast, but patients must be informed of the risk for depression before initiating therapy. Cyclosporine is contraindicated in patients with prior psoralen plus UVA (PUVA) treatment or radiation therapy, abnormal renal function, uncontrolled hypertension, uncontrolled and active infections, and a history of systemic malignancy. Live vaccines should be avoided in patients on cyclosporine, and caution is advised when cyclosporine is prescribed for patients with poorly controlled diabetes.

Pretreatment Screening

Because of drug interactions, a detailed medication history is essential prior to starting any systemic medication for psoriasis. Apremilast and cyclosporine are metabolized by cytochrome P450 and therefore are more susceptible to drug-related interactions. Cyclosporine use can affect levels of other medications that are metabolized by cytochrome P450, such as statins, calcium channel blockers, and warfarin. Similarly, acitretin’s metabolism is affected by drugs that interfere with cytochrome P450. Additionally, screening laboratory tests are needed before initiating systemic nonbiologic agents for psoriasis, with the exception of apremilast.

Prior to initiating methotrexate treatment, patients may require tuberculosis (TB), hepatitis B, and hepatitis C screening tests, depending on their risk factors. A baseline liver fibrosis assessment is recommended because of the potential of hepatotoxicity in patients receiving methotrexate. Noninvasive serology tests utilized to evaluate the presence of pre-existing liver disease include Fibrosis-4, FibroMeter, FibroSure, and Hepascore. Patients with impaired renal function have an increased predisposition to methotrexate-induced hematologic toxicity. Thus, it is necessary to administer a test dose of methotrexate in these patients followed by a complete blood cell count (CBC) 5 to 7 days later. An unremarkable CBC after the test dose suggests the absence of myelosuppression, and methotrexate dosage can be increased weekly. Patients on methotrexate also must receive folate supplementation to reduce the risk for adverse effects during treatment.

Patients considering cyclosporine must undergo screening for family and personal history of renal disease. Prior to initiating treatment, patients require 2 blood pressure measurements, hepatitis screening, TB screening, urinalysis, serum creatinine (Cr), blood urea nitrogen (BUN), CBC, potassium and magnesium levels, uric acid levels, lipid profile, bilirubin, and liver function tests (LFTs). A pregnancy test also is warranted for women of childbearing potential (WOCP).

Patients receiving acitretin should receive screening laboratory tests consisting of fasting cholesterol and triglycerides, CBC, renal function tests, LFTs, and a pregnancy test, if applicable.

After baseline evaluations, the selected oral systemic can be initiated using specific dosing regimens to ensure optimal drug efficacy and reduce incidence of adverse effects (eTable).

Monitoring During Active Treatment

Physicians need to counsel patients on potential adverse effects of their medications. Because of its relatively safe profile among the systemic nonbiologic agents, apremilast requires the least monitoring during treatment. There is no required routine laboratory monitoring for patients using apremilast, though testing may be pursued at the clinician’s discretion. However, weight should be regularly measured in patients on apremilast. In a phase 3 clinical trial of patients with psoriasis, 12% of patients on apremilast experienced a 5% to 10% weight loss compared to 5% of patients on placebo.^11,13 Thus, it is recommended that physicians consider discontinuing apremilast in patients with a weight loss of more than 5% from baseline, especially if it may lead to other unfavorable health effects. Because depression is reported among 1% of patients on apremilast, close monitoring for new or worsening symptoms of depression should be performed during treatment.^11,13 To avoid common GI side effects, apremilast is initiated at 10 mg/d and is increased by 10 mg/d over the first 5 days to a final dose of 30 mg BID. Elderly patients in particular should be cautioned about the risk of dehydration associated with GI side effects. Patients with severe renal impairment (Cr clearance, <30 mL/min) should use apremilast at a dosage of 30 mg once daily.

For patients on methotrexate, laboratory monitoring is essential after each dose increase. It also is important for physicians to obtain regular blood work to assess for hematologic abnormalities and hepatoxicity. Patients with risk factors such as renal insufficiency, increased age, hypoalbuminemia, alcohol abuse and alcoholic liver disease, and methotrexate dosing errors, as well as those prone to drug-related interactions, must be monitored closely for pancytopenia.^14,15 The protocol for screening for methotrexate-induced hepatotoxicity during treatment depends on patient risk factors. Risk factors for hepatoxicity include history of or current alcohol abuse, abnormal LFTs, personal or family history of liver disease, diabetes, obesity, use of other hepatotoxic drugs, and hyperlipidemia.¹⁶ In patients without blood work abnormalities, CBC and LFTs can be performed every 3 to 6 months. Patients with abnormally elevated LFTs require repeat blood work every 2 to 4 weeks. Persistent elevations in LFTs require further evaluation by a GI specialist. After a cumulative dose of 3.5 to 4 g, patients should receive a GI referral and further studies (such as vibration-controlled transient elastography or liver biopsy) to assess for liver fibrosis. Patients with signs of stage 3 liver fibrosis are recommended to discontinue methotrexate and switch to another medication for psoriasis. For patients with impaired renal function, periodic BUN and Cr monitoring are needed. Common adverse effects of methotrexate include diarrhea, nausea, and anorexia, which can be mitigated by taking methotrexate with food or lowering the dosage.⁸ Patients on methotrexate should be monitored for rare but potential risks of infection and reactivation of latent TB, hepatitis, and lymphoma. To reduce the incidence of methotrexate toxicity from drug interactions, a review of current medications at each follow-up visit is recommended.

Nephrotoxicity and hypertension are the most common adverse effects of cyclosporine. It is important to monitor BUN and Cr biweekly for the initial 3 months, then at monthly intervals if there are no persistent abnormalities. Patients also must receive monthly CBC, potassium and magnesium levels, uric acid levels, lipid panel, serum bilirubin, and LFTs to monitor for adverse effects.¹⁷ Physicians should obtain regular pregnancy tests in WOCP. Weekly monitoring of early-morning blood pressure is recommended for patients on cyclosporine to detect early cyclosporine-induced nephrotoxicity. Hypertension on 2 separate occasions warrants a reduction in cyclosporine dosage or an addition of a calcium channel blocker for blood pressure control. Dose reduction also should be performed in patients with an increase in Cr above baseline greater than 25%.¹⁷ If Cr level is persistently elevated or if blood pressure does not normalize to lower than 140/90 after dose reduction, cyclosporine should be immediately discontinued. Patients on cyclosporine for more than a year warrant an annual estimation of glomerular filtration rate because of irreversible kidney damage associated with long-term use. A systematic review of patients treated with cyclosporine for more than 2 years found that at least 50% of patients experienced a 30% increase in Cr above baseline.¹⁸

Patients taking acitretin should be monitored for hyperlipidemia, the most common laboratory abnormality seen in 25% to 50% of patients.¹⁹ Fasting lipid panel and LFTs should be performed monthly for the initial 3 months on acitretin, then at 3-month intervals. Lifestyle changes should be encouraged to reduce hyperlipidemia, and fibrates may be given to treat elevated triglyceride levels, the most common type of hyperlipidemia seen with acitretin. Acitretin-induced toxic hepatitis is a rare occurrence that warrants immediate discontinuation of the medication.²⁰ Monthly pregnancy tests must be performed in WOCP.

Combination Therapy

For apremilast, there is anecdotal evidence supporting its use in conjunction with phototherapy or biologics in some cases, but no high-quality data.²¹ On the other hand, using combination therapy with other systemic therapies can reduce adverse effects and decrease the amount of medication needed to achieve psoriasis clearance. Methotrexate used with etanercept, for example, has been more effective than methotrexate monotherapy in treating psoriasis, which has been attributed to a methotrexate-mediated reduction in the production of antidrug antibodies.^22,23

Methotrexate, cyclosporine, and acitretin have synergistic effects when used with phototherapy. Narrowband UVB (NB-UVB) phototherapy combined with methotrexate is more effective in clearing psoriasis than methotrexate or NB-UVB phototherapy alone. Similarly, acitretin and PUVA combination therapy is more effective than acitretin or PUVA phototherapy alone. Combination regimens of acitretin and broadband UVB phototherapy, acitretin and NB-UVB phototherapy, and acitretin and PUVA phototherapy also have been more effective than individual modalities alone. Combination therapy reduces the cumulative doses of both therapies and reduces the frequency and duration of phototherapy needed for psoriatic clearance.²⁴ In acitretin combination therapy with UVB phototherapy, the recommended regimen is 2 weeks of acitretin monotherapy followed by UVB phototherapy. For patients with an inadequate response to UVB phototherapy, the UVB dose can be reduced by 30% to 50%, and acitretin 25 mg/d can be added to phototherapy treatment. Acitretin-UVB combination therapy has been shown to reduce the risk of UVB-induced erythema seen in UVB monotherapy. Similarly, the risk of squamous cell carcinoma is reduced in acitretin-PUVA combination therapy compared to PUVA monotherapy.²⁵

The timing of phototherapy in combination with systemic nonbiologic agents is critical. Phototherapy used simultaneously with cyclosporine is contraindicated owing to increased risk of photocarcinogenesis, whereas phototherapy used in sequence with cyclosporine is well tolerated and effective. Furthermore, cyclosporine 3 mg/kg/d for 4 weeks followed by a rapid cyclosporine taper and initiation of NB-UVB phototherapy demonstrated resolution of psoriasis with fewer NB-UVB treatments and less UVB exposure than NB-UVB therapy alone.²⁶

Final Thoughts

The FDA-approved systemic nonbiologic agents are accessible and effective treatment options for adults with widespread or inadequately controlled psoriasis. Selecting the ideal therapy requires careful consideration of medication toxicity, contraindications, monitoring requirements, and patient comorbidities. The AAD-NPF guidelines guide dermatologists in prescribing systemic nonbiologic treatments in adults with psoriasis. Utilizing these recommendations in combination with clinician judgment will help patients achieve safe and optimal psoriasis clearance.

In Part 1 of this article in the December 2020 issue of OBG Management, I discussed the reasons that pessaries are an effective treatment option for many women with pelvic organ prolapse (POP) and stress urinary incontinence (SUI) and provided details on the types of pessaries available.

In this article, I highlight the steps in fitting a pessary, pessary aftercare, and potential complications associated with pessary use. In addition, I discuss the effectiveness of pessary treatment for POP and SUI as well as for preterm labor prevention and defecatory disorders.

The pessary fitting process

For a given patient, the best size pessary is the smallest one that will not fall out. The only “rule” for fitting a pessary is that a woman’s internal vaginal caliber should be wider than her introitus.

When fitting a pessary, goals include that the selected pessary:

• should be comfortable for the patient to wear
• is not easily expelled
• does not interfere with urination or defecation
• does not cause vaginal irritation.

The presence or absence of a cervix or uterus does not affect pessary choice.

Most experts agree that the process for fitting the right size pessary is one of trial and error. As with fitting a contraceptive diaphragm, the clinician should perform a manual examination to estimate the integrity and width of the perineum and the depth of the vagina to roughly approximate the pessary size that might best fit. Using a set of “fitting pessaries,” a pessary of the estimated size should be placed into the vagina and the fit evaluated as to whether the device is too big, too small, or appropriate. If the pessary is easily expelled, larger sizes should be tried until the pessary remains in place or the patient is uncomfortable. Once the pessary is in place, the clinician should be able to run his or her finger around the entire pessary; if this is not possible, the pessary is too tight. In addition, the pessary should remain more than one finger breadth above the introitus when the patient is standing or bearing down.

Since many patients who require a pessary are elderly, their perineal skin and vaginal mucosa may be atrophic and fragile. Inserting a pessary can be uncomfortable and can cause abrasions or tears. Successfully fitting a pessary may require extra care under these circumstances. The following steps may help alleviate these difficulties:

• Explain the fitting process to the patient in detail.
• Employ lubrication liberally.
• Enlarge the introitus by applying gentle digital pressure on the posterior fourchette.
• Apply 2% lidocaine ointment several minutes prior to pessary fitting to help decrease patient discomfort.
• Treat the patient for several weeks with vaginal estrogen cream before attempting to fit a pessary if severe vulvovaginal atrophy is present.

Once the type and size of the pessary are selected and a pessary is inserted, evaluate the patient with the pessary in place. Assess for the following:

Discomfort. Ask the patient if she feels discomfort with the pessary in position. A patient with a properly fitting pessary should not feel that it is in place. If she does feel discomfort initially, the discomfort will only increase with time and the issue should be addressed at that time.

Expulsion. Test to make certain that the pessary is not easily expelled from the vagina. Have the patient walk, cough, squat, and even jump if possible.

Urination. Have the patient urinate with the pessary in place. This tests for her ability to void while wearing the pessary and shows whether the contraction of pelvic muscles during voiding results in expulsion of the pessary. (Experience shows that it is best to do this with a plastic “hat” over the toilet so that if the pessary is expelled, it does not drop into the bowl.)

Re-examination. After these provocative tests, examine the patient again to ensure that the pessary has not slid out of place.

Depending on whether or not your office stocks pessaries, at this point the patient is either given the correct type and size of pessary or it is ordered for her. If the former, the patient should try placing it herself; if she is unable to, the clinician should place it for her. In either event, its position should be checked. If the pessary has to be ordered, the patient must schedule an appointment to return for pessary insertion.

Whether the pessary is supplied by the office or ordered, instruct the patient on how to insert and remove the pessary, how frequently to remove it for cleansing (see below), and signs to watch for, such as vaginal bleeding, inability to void or defecate, or pelvic pain.

It is advisable to schedule a subsequent visit for 2 to 3 weeks after initial pessary placement to assess how the patient is doing and to address any issues that have developed.

Continue to: Special circumstances...

It is safe for a patient with a pessary in place to undergo magnetic resonance imaging.¹ Patients should be informed, however, that full body scans, such as at airports, will detect pessaries. Patients may need to obtain a physician’s note to document that the pessary is a medical device.

Finally, several factors may prevent successful pessary fitting. These include prior pelvic surgery, obesity, short vaginal length (less than 6–7 cm), and a vaginal introitus width of greater than 4 finger breadths.

Necessary pessary aftercare

Once a pessary is in place and the patient is comfortable with it, the only maintenance necessary is the pessary’s intermittent removal for cleansing and for evaluation of the vaginal mucosa for erosion and ulcerations. How frequently this should be done varies based on the type of pessary, the amount of discharge that a woman produces, whether or not an odor develops after prolonged wearing of the pessary, and whether or not the patient’s vaginal mucosa has been abraded.

The question of timing for pessary cleaning

Although there are many opinions about how often pessaries should be removed and cleaned, no data in the literature support any specific interval. Pessaries that are easily removed by women themselves can be cleaned as frequently as desired, often on a weekly basis. The patient simply removes the pessary, washes it with soap and water, and reinserts it. For pessaries that are difficult to remove (such as the Gellhorn, cube, or donut) or for women who are physically unable to remove their own ring pessary, the clinician should remove and clean the pessary in the office every 3 to 6 months. It has been shown that there is no difference in complications from pessary use with either of these intervals.²

Prior to any vaginal surgical procedure, patients must be instructed to remove their pessary 10 to 14 days beforehand so that the surgeon can see the full extent of prolapse when making decisions about reconstruction and so that any vaginal mucosal erosions or abrasions have time to heal.

Office visits for follow-up care

The pessary “cleaning visit” has several goals, including to:

• see if the pessary is meeting the patient’s needs in terms of resolving symptoms of prolapse and/or restoring urinary continence
• discuss with the patient any problems she may be having, such as pelvic discomfort or pressure, difficulty voiding or defecating, excessive vaginal discharge, or vaginal odor
• check for vaginal mucosal erosion or ulceration; such vaginal lesions often can be prevented by the prophylactic use of either estrogen vaginal cream twice weekly or the continuous use of an estradiol vaginal ring in addition to the pessary
• evaluate the condition of the pessary itself and clean it with soap and water.

Continue to: Potential complications of pessary use...

The most common complications experienced by pessary users are:

Odor or excessive discharge. Bacterial vaginosis (BV) occurs more frequently in women who use pessaries. The symptoms of BV can be minimized—but unfortunately not totally eliminated—by the prophylactic use of antiseptic vaginal creams or gels, such as metronidazole, clindamycin, Trimo-San (oxyquinoline sulfate and sodium lauryl sulfate), and others. Inserting the gel vaginally once a week can significantly reduce discharge and odor.³

Vaginal mucosal erosion and ulceration. These are treated by removing the pessary for 2 weeks during which time estrogen cream is applied daily or an estradiol vaginal ring is put in place. If no resolution occurs after 2 weeks, the nonhealing vaginal mucosa should be biopsied.

Pressure on the rectum or bladder. If the pessary causes significant discomfort or interferes with voiding function, then either a different size or a different type pessary should be tried

Patients may discontinue pessary use for a variety of reasons. Among these are:

• discomfort
• inadequate improvement of POP or incontinence symptoms
• expulsion of the pessary during daily activities
• the patient’s desire for surgery instead
• worsening of urine leakage
• difficulty inserting or removing the pessary
• damage to the vaginal mucosa
• pain during removal of the pessary in the office.

Pessary effectiveness for POP and SUI symptoms

As might be expected with a device that is available in so many forms and is used to treat varied types of POP and SUI, the data concerning the success rates of pessary use vary considerably. These rates depend on the definition of success, that is, complete or partial control of prolapse and/or incontinence; which devices are being evaluated; and the nature and severity of the POP and/or SUI being treated.

That being said, a review of the literature reveals that the rates of prolapse symptom relief vary from 48% to 92% (TABLE 1).^4-13

As for success in relieving symptoms of incontinence, studies show improvements in from 40% to 77% of patients (TABLE 2).^6,8,14-17

In addition, some studies show a 50% improvement in bowel symptoms (urgency, obstruction, and anal incontinence) with the use of a pessary.^9,18

How pessaries compare with surgery

While surgery has the advantage of being a one-time fix with a very high rate of initial success in correcting both POP and incontinence, surgery also has potential drawbacks:

• It is an invasive procedure with the discomfort and risk of complications any surgery entails.
• There is a relatively high rate of prolapse recurrence.
• It exposes the patient to the possibility of mesh erosion if mesh is employed either for POP support or incontinence treatment.

Pessaries, on the other hand, are inexpensive, nonsurgical, removable, and allow for immediate correction of symptoms. Moreover, if the pessary is tried and is found to be unsatisfactory, surgery always can be performed subsequently.

Drawbacks of pessary treatment compared with surgery include the:

• ongoing need to wear an artificial internal device
• need for intermittent pessary removal and cleansing
• inability to have sexual intercourse with certain kinds of pessaries in place
• possible accumulation of vaginal discharge and odor.

Sexual activity and pessaries

Studies by Fernando, Meriwether, and Kuhn concur that for a substantial number of pessary users who are sexually active, both frequency and satisfaction with sexual intercourse are increased.^8,19,20 Kuhn further showed that desire, orgasm, and lubrication improved with the use of pessaries.²⁰ While some types of pessaries do require removal for intercourse, Clemons reported that issues involving sexual activity are not associated with pessary discontinuation.²¹

Using a pessary to predict a surgical outcome

Because a pessary elevates the pelvic organs, supports the vaginal walls, and lifts the bladder and urethra into a position that simulates the results of surgical repair, trial placement of a pessary can be used as a fairly accurate predictive tool to model what pelvic support and continence status will be after a proposed surgical procedure.^22,23 This is especially important because a significant number of patients with POP will have their occult stress incontinence unmasked following a reparative procedure.²⁴ A brief pessary trial prior to surgery, therefore, can be a useful tool for both patient and surgeon.

Continue to: Pessaries for prevention of preterm labor...

Pessaries for prevention of preterm labor

Almost 1 in 10 births in the United States occurs before 37 completed weeks of gestation.²⁵ Obstetricians have long thought that in women at risk for preterm delivery, the use of a pessary might help reduce the pressure of the growing uterus on the cervix and thus help prevent premature cervical dilation. It also has been thought that use of a pessary would be a safer and less invasive alternative to cervical cerclage. Many studies have evaluated the use of pessaries for the prevention of preterm labor with a mixture of positive (TABLE 3)^26-29 and negative results (TABLE 4).^30-33

From these data, it is reasonable to conclude that:

• The final answer concerning the effectiveness or lack thereof of pessary use in preventing preterm delivery is not yet in.
• Any advantage there might be to using pessaries to prevent preterm delivery cannot be too significant if multiple studies show as many negative outcomes as positive ones.

Pessary effectiveness in defecatory disorders

Vaginal birth has the potential to create multiple anatomic injuries in the anus, lower pelvis, and perineum that can affect defecation and bowel control. Tears of the anal sphincter, whether obvious or occult, may heal incompletely or be repaired inadequately.³⁴ Nerve innervation of the perianal and perineal areas can be interrupted or damaged by stretching, tearing, or prolonged compression. Of healthy parous adult women, 7% to 16% admit incontinence of gas or feces.^35,36

In addition, when a rectocele is present, stool in the lower rectum may cause bulging of the anterior rectal wall into the vagina, preventing stool from passing out of the anus. This sometimes requires women to digitally press their posterior vaginal walls during defecation to evacuate stool successfully. The question thus arises as to whether or not pessary placement and subsequent relief of rectoceles might facilitate bowel movements and decrease or eliminate defecatory dysfunction.

As with the issue of pessary use for prevention of preterm delivery, the answer is mixed. For instance, while Brazell¹⁸ showed that there was an overall improvement in bowel symptoms in pessary users, a study by Komesu¹⁰ did not demonstrate improvement.

There is, however, a relatively new device specifically designed to control defecatory problems: the vaginal bowel control system (Eclipse; Pelvalon). The silicon device is placed intravaginally as one does a pessary. After insertion, it is inflated via a valve and syringe. It works by putting pressure on and reversibly closing the lower rectum, thus blocking the uncontrolled passage of stool and gas. It can be worn continuously or intermittently, but it does need to be deflated for normal bowel movements. One trial of this device demonstrated a 50% reduction in incontinence episodes with a patient satisfaction rate of 84% at 3 months.³⁷ This device may well prove to be a valuable nonsurgical approach to the treatment of fecal incontinence. Unfortunately, the device is relatively expensive and usually is not covered by insurance as third-party payers do not consider it to be a pessary (which generally is covered).

Practice management particulars

Useful information on Current Procedural Terminology codes for pessaries, diagnostic codes, and the cost of various pessaries is provided in TABLE 5,³⁸TABLE 6,³⁹ and TABLE 7.^40-42

A contemporary device used since antiquity

Pessaries, considered “old-fashioned” by many gynecologists, are actually a very cost-effective and useful tool for the correction of POP and SUI. It behooves all who provide medical care to women to be familiar with them, to know when they might be useful, and to know how to fit and prescribe them. ●

In Part 1 of this article in the December 2020 issue of OBG Management, I discussed the reasons that pessaries are an effective treatment option for many women with pelvic organ prolapse (POP) and stress urinary incontinence (SUI) and provided details on the types of pessaries available.

In this article, I highlight the steps in fitting a pessary, pessary aftercare, and potential complications associated with pessary use. In addition, I discuss the effectiveness of pessary treatment for POP and SUI as well as for preterm labor prevention and defecatory disorders.

The pessary fitting process

For a given patient, the best size pessary is the smallest one that will not fall out. The only “rule” for fitting a pessary is that a woman’s internal vaginal caliber should be wider than her introitus.

When fitting a pessary, goals include that the selected pessary:

• should be comfortable for the patient to wear
• is not easily expelled
• does not interfere with urination or defecation
• does not cause vaginal irritation.

The presence or absence of a cervix or uterus does not affect pessary choice.

Most experts agree that the process for fitting the right size pessary is one of trial and error. As with fitting a contraceptive diaphragm, the clinician should perform a manual examination to estimate the integrity and width of the perineum and the depth of the vagina to roughly approximate the pessary size that might best fit. Using a set of “fitting pessaries,” a pessary of the estimated size should be placed into the vagina and the fit evaluated as to whether the device is too big, too small, or appropriate. If the pessary is easily expelled, larger sizes should be tried until the pessary remains in place or the patient is uncomfortable. Once the pessary is in place, the clinician should be able to run his or her finger around the entire pessary; if this is not possible, the pessary is too tight. In addition, the pessary should remain more than one finger breadth above the introitus when the patient is standing or bearing down.

Since many patients who require a pessary are elderly, their perineal skin and vaginal mucosa may be atrophic and fragile. Inserting a pessary can be uncomfortable and can cause abrasions or tears. Successfully fitting a pessary may require extra care under these circumstances. The following steps may help alleviate these difficulties:

• Explain the fitting process to the patient in detail.
• Employ lubrication liberally.
• Enlarge the introitus by applying gentle digital pressure on the posterior fourchette.
• Apply 2% lidocaine ointment several minutes prior to pessary fitting to help decrease patient discomfort.
• Treat the patient for several weeks with vaginal estrogen cream before attempting to fit a pessary if severe vulvovaginal atrophy is present.

Once the type and size of the pessary are selected and a pessary is inserted, evaluate the patient with the pessary in place. Assess for the following:

Discomfort. Ask the patient if she feels discomfort with the pessary in position. A patient with a properly fitting pessary should not feel that it is in place. If she does feel discomfort initially, the discomfort will only increase with time and the issue should be addressed at that time.

Expulsion. Test to make certain that the pessary is not easily expelled from the vagina. Have the patient walk, cough, squat, and even jump if possible.

Urination. Have the patient urinate with the pessary in place. This tests for her ability to void while wearing the pessary and shows whether the contraction of pelvic muscles during voiding results in expulsion of the pessary. (Experience shows that it is best to do this with a plastic “hat” over the toilet so that if the pessary is expelled, it does not drop into the bowl.)

Re-examination. After these provocative tests, examine the patient again to ensure that the pessary has not slid out of place.

Depending on whether or not your office stocks pessaries, at this point the patient is either given the correct type and size of pessary or it is ordered for her. If the former, the patient should try placing it herself; if she is unable to, the clinician should place it for her. In either event, its position should be checked. If the pessary has to be ordered, the patient must schedule an appointment to return for pessary insertion.

Whether the pessary is supplied by the office or ordered, instruct the patient on how to insert and remove the pessary, how frequently to remove it for cleansing (see below), and signs to watch for, such as vaginal bleeding, inability to void or defecate, or pelvic pain.

It is advisable to schedule a subsequent visit for 2 to 3 weeks after initial pessary placement to assess how the patient is doing and to address any issues that have developed.

Continue to: Special circumstances...

It is safe for a patient with a pessary in place to undergo magnetic resonance imaging.¹ Patients should be informed, however, that full body scans, such as at airports, will detect pessaries. Patients may need to obtain a physician’s note to document that the pessary is a medical device.

Finally, several factors may prevent successful pessary fitting. These include prior pelvic surgery, obesity, short vaginal length (less than 6–7 cm), and a vaginal introitus width of greater than 4 finger breadths.

Necessary pessary aftercare

Once a pessary is in place and the patient is comfortable with it, the only maintenance necessary is the pessary’s intermittent removal for cleansing and for evaluation of the vaginal mucosa for erosion and ulcerations. How frequently this should be done varies based on the type of pessary, the amount of discharge that a woman produces, whether or not an odor develops after prolonged wearing of the pessary, and whether or not the patient’s vaginal mucosa has been abraded.

The question of timing for pessary cleaning

Although there are many opinions about how often pessaries should be removed and cleaned, no data in the literature support any specific interval. Pessaries that are easily removed by women themselves can be cleaned as frequently as desired, often on a weekly basis. The patient simply removes the pessary, washes it with soap and water, and reinserts it. For pessaries that are difficult to remove (such as the Gellhorn, cube, or donut) or for women who are physically unable to remove their own ring pessary, the clinician should remove and clean the pessary in the office every 3 to 6 months. It has been shown that there is no difference in complications from pessary use with either of these intervals.²

Prior to any vaginal surgical procedure, patients must be instructed to remove their pessary 10 to 14 days beforehand so that the surgeon can see the full extent of prolapse when making decisions about reconstruction and so that any vaginal mucosal erosions or abrasions have time to heal.

Office visits for follow-up care

The pessary “cleaning visit” has several goals, including to:

• see if the pessary is meeting the patient’s needs in terms of resolving symptoms of prolapse and/or restoring urinary continence
• discuss with the patient any problems she may be having, such as pelvic discomfort or pressure, difficulty voiding or defecating, excessive vaginal discharge, or vaginal odor
• check for vaginal mucosal erosion or ulceration; such vaginal lesions often can be prevented by the prophylactic use of either estrogen vaginal cream twice weekly or the continuous use of an estradiol vaginal ring in addition to the pessary
• evaluate the condition of the pessary itself and clean it with soap and water.

Continue to: Potential complications of pessary use...

The most common complications experienced by pessary users are:

Odor or excessive discharge. Bacterial vaginosis (BV) occurs more frequently in women who use pessaries. The symptoms of BV can be minimized—but unfortunately not totally eliminated—by the prophylactic use of antiseptic vaginal creams or gels, such as metronidazole, clindamycin, Trimo-San (oxyquinoline sulfate and sodium lauryl sulfate), and others. Inserting the gel vaginally once a week can significantly reduce discharge and odor.³

Vaginal mucosal erosion and ulceration. These are treated by removing the pessary for 2 weeks during which time estrogen cream is applied daily or an estradiol vaginal ring is put in place. If no resolution occurs after 2 weeks, the nonhealing vaginal mucosa should be biopsied.

Pressure on the rectum or bladder. If the pessary causes significant discomfort or interferes with voiding function, then either a different size or a different type pessary should be tried

Patients may discontinue pessary use for a variety of reasons. Among these are:

• discomfort
• inadequate improvement of POP or incontinence symptoms
• expulsion of the pessary during daily activities
• the patient’s desire for surgery instead
• worsening of urine leakage
• difficulty inserting or removing the pessary
• damage to the vaginal mucosa
• pain during removal of the pessary in the office.

Pessary effectiveness for POP and SUI symptoms

As might be expected with a device that is available in so many forms and is used to treat varied types of POP and SUI, the data concerning the success rates of pessary use vary considerably. These rates depend on the definition of success, that is, complete or partial control of prolapse and/or incontinence; which devices are being evaluated; and the nature and severity of the POP and/or SUI being treated.

That being said, a review of the literature reveals that the rates of prolapse symptom relief vary from 48% to 92% (TABLE 1).^4-13

As for success in relieving symptoms of incontinence, studies show improvements in from 40% to 77% of patients (TABLE 2).^6,8,14-17

In addition, some studies show a 50% improvement in bowel symptoms (urgency, obstruction, and anal incontinence) with the use of a pessary.^9,18

How pessaries compare with surgery

While surgery has the advantage of being a one-time fix with a very high rate of initial success in correcting both POP and incontinence, surgery also has potential drawbacks:

• It is an invasive procedure with the discomfort and risk of complications any surgery entails.
• There is a relatively high rate of prolapse recurrence.
• It exposes the patient to the possibility of mesh erosion if mesh is employed either for POP support or incontinence treatment.

Pessaries, on the other hand, are inexpensive, nonsurgical, removable, and allow for immediate correction of symptoms. Moreover, if the pessary is tried and is found to be unsatisfactory, surgery always can be performed subsequently.

Drawbacks of pessary treatment compared with surgery include the:

• ongoing need to wear an artificial internal device
• need for intermittent pessary removal and cleansing
• inability to have sexual intercourse with certain kinds of pessaries in place
• possible accumulation of vaginal discharge and odor.

Sexual activity and pessaries

Studies by Fernando, Meriwether, and Kuhn concur that for a substantial number of pessary users who are sexually active, both frequency and satisfaction with sexual intercourse are increased.^8,19,20 Kuhn further showed that desire, orgasm, and lubrication improved with the use of pessaries.²⁰ While some types of pessaries do require removal for intercourse, Clemons reported that issues involving sexual activity are not associated with pessary discontinuation.²¹

Using a pessary to predict a surgical outcome

Because a pessary elevates the pelvic organs, supports the vaginal walls, and lifts the bladder and urethra into a position that simulates the results of surgical repair, trial placement of a pessary can be used as a fairly accurate predictive tool to model what pelvic support and continence status will be after a proposed surgical procedure.^22,23 This is especially important because a significant number of patients with POP will have their occult stress incontinence unmasked following a reparative procedure.²⁴ A brief pessary trial prior to surgery, therefore, can be a useful tool for both patient and surgeon.

Continue to: Pessaries for prevention of preterm labor...

Pessaries for prevention of preterm labor

Almost 1 in 10 births in the United States occurs before 37 completed weeks of gestation.²⁵ Obstetricians have long thought that in women at risk for preterm delivery, the use of a pessary might help reduce the pressure of the growing uterus on the cervix and thus help prevent premature cervical dilation. It also has been thought that use of a pessary would be a safer and less invasive alternative to cervical cerclage. Many studies have evaluated the use of pessaries for the prevention of preterm labor with a mixture of positive (TABLE 3)^26-29 and negative results (TABLE 4).^30-33

From these data, it is reasonable to conclude that:

• The final answer concerning the effectiveness or lack thereof of pessary use in preventing preterm delivery is not yet in.
• Any advantage there might be to using pessaries to prevent preterm delivery cannot be too significant if multiple studies show as many negative outcomes as positive ones.

Pessary effectiveness in defecatory disorders

Vaginal birth has the potential to create multiple anatomic injuries in the anus, lower pelvis, and perineum that can affect defecation and bowel control. Tears of the anal sphincter, whether obvious or occult, may heal incompletely or be repaired inadequately.³⁴ Nerve innervation of the perianal and perineal areas can be interrupted or damaged by stretching, tearing, or prolonged compression. Of healthy parous adult women, 7% to 16% admit incontinence of gas or feces.^35,36

In addition, when a rectocele is present, stool in the lower rectum may cause bulging of the anterior rectal wall into the vagina, preventing stool from passing out of the anus. This sometimes requires women to digitally press their posterior vaginal walls during defecation to evacuate stool successfully. The question thus arises as to whether or not pessary placement and subsequent relief of rectoceles might facilitate bowel movements and decrease or eliminate defecatory dysfunction.

As with the issue of pessary use for prevention of preterm delivery, the answer is mixed. For instance, while Brazell¹⁸ showed that there was an overall improvement in bowel symptoms in pessary users, a study by Komesu¹⁰ did not demonstrate improvement.

There is, however, a relatively new device specifically designed to control defecatory problems: the vaginal bowel control system (Eclipse; Pelvalon). The silicon device is placed intravaginally as one does a pessary. After insertion, it is inflated via a valve and syringe. It works by putting pressure on and reversibly closing the lower rectum, thus blocking the uncontrolled passage of stool and gas. It can be worn continuously or intermittently, but it does need to be deflated for normal bowel movements. One trial of this device demonstrated a 50% reduction in incontinence episodes with a patient satisfaction rate of 84% at 3 months.³⁷ This device may well prove to be a valuable nonsurgical approach to the treatment of fecal incontinence. Unfortunately, the device is relatively expensive and usually is not covered by insurance as third-party payers do not consider it to be a pessary (which generally is covered).

Practice management particulars

Useful information on Current Procedural Terminology codes for pessaries, diagnostic codes, and the cost of various pessaries is provided in TABLE 5,³⁸TABLE 6,³⁹ and TABLE 7.^40-42

A contemporary device used since antiquity

Pessaries, considered “old-fashioned” by many gynecologists, are actually a very cost-effective and useful tool for the correction of POP and SUI. It behooves all who provide medical care to women to be familiar with them, to know when they might be useful, and to know how to fit and prescribe them. ●

In Part 1 of this article in the December 2020 issue of OBG Management, I discussed the reasons that pessaries are an effective treatment option for many women with pelvic organ prolapse (POP) and stress urinary incontinence (SUI) and provided details on the types of pessaries available.

In this article, I highlight the steps in fitting a pessary, pessary aftercare, and potential complications associated with pessary use. In addition, I discuss the effectiveness of pessary treatment for POP and SUI as well as for preterm labor prevention and defecatory disorders.

The pessary fitting process

For a given patient, the best size pessary is the smallest one that will not fall out. The only “rule” for fitting a pessary is that a woman’s internal vaginal caliber should be wider than her introitus.

When fitting a pessary, goals include that the selected pessary:

• should be comfortable for the patient to wear
• is not easily expelled
• does not interfere with urination or defecation
• does not cause vaginal irritation.

The presence or absence of a cervix or uterus does not affect pessary choice.

Most experts agree that the process for fitting the right size pessary is one of trial and error. As with fitting a contraceptive diaphragm, the clinician should perform a manual examination to estimate the integrity and width of the perineum and the depth of the vagina to roughly approximate the pessary size that might best fit. Using a set of “fitting pessaries,” a pessary of the estimated size should be placed into the vagina and the fit evaluated as to whether the device is too big, too small, or appropriate. If the pessary is easily expelled, larger sizes should be tried until the pessary remains in place or the patient is uncomfortable. Once the pessary is in place, the clinician should be able to run his or her finger around the entire pessary; if this is not possible, the pessary is too tight. In addition, the pessary should remain more than one finger breadth above the introitus when the patient is standing or bearing down.

Since many patients who require a pessary are elderly, their perineal skin and vaginal mucosa may be atrophic and fragile. Inserting a pessary can be uncomfortable and can cause abrasions or tears. Successfully fitting a pessary may require extra care under these circumstances. The following steps may help alleviate these difficulties:

• Explain the fitting process to the patient in detail.
• Employ lubrication liberally.
• Enlarge the introitus by applying gentle digital pressure on the posterior fourchette.
• Apply 2% lidocaine ointment several minutes prior to pessary fitting to help decrease patient discomfort.
• Treat the patient for several weeks with vaginal estrogen cream before attempting to fit a pessary if severe vulvovaginal atrophy is present.

Once the type and size of the pessary are selected and a pessary is inserted, evaluate the patient with the pessary in place. Assess for the following:

Discomfort. Ask the patient if she feels discomfort with the pessary in position. A patient with a properly fitting pessary should not feel that it is in place. If she does feel discomfort initially, the discomfort will only increase with time and the issue should be addressed at that time.

Expulsion. Test to make certain that the pessary is not easily expelled from the vagina. Have the patient walk, cough, squat, and even jump if possible.

Urination. Have the patient urinate with the pessary in place. This tests for her ability to void while wearing the pessary and shows whether the contraction of pelvic muscles during voiding results in expulsion of the pessary. (Experience shows that it is best to do this with a plastic “hat” over the toilet so that if the pessary is expelled, it does not drop into the bowl.)

Re-examination. After these provocative tests, examine the patient again to ensure that the pessary has not slid out of place.

Depending on whether or not your office stocks pessaries, at this point the patient is either given the correct type and size of pessary or it is ordered for her. If the former, the patient should try placing it herself; if she is unable to, the clinician should place it for her. In either event, its position should be checked. If the pessary has to be ordered, the patient must schedule an appointment to return for pessary insertion.

Whether the pessary is supplied by the office or ordered, instruct the patient on how to insert and remove the pessary, how frequently to remove it for cleansing (see below), and signs to watch for, such as vaginal bleeding, inability to void or defecate, or pelvic pain.

It is advisable to schedule a subsequent visit for 2 to 3 weeks after initial pessary placement to assess how the patient is doing and to address any issues that have developed.

Continue to: Special circumstances...

It is safe for a patient with a pessary in place to undergo magnetic resonance imaging.¹ Patients should be informed, however, that full body scans, such as at airports, will detect pessaries. Patients may need to obtain a physician’s note to document that the pessary is a medical device.

Finally, several factors may prevent successful pessary fitting. These include prior pelvic surgery, obesity, short vaginal length (less than 6–7 cm), and a vaginal introitus width of greater than 4 finger breadths.

Necessary pessary aftercare

Once a pessary is in place and the patient is comfortable with it, the only maintenance necessary is the pessary’s intermittent removal for cleansing and for evaluation of the vaginal mucosa for erosion and ulcerations. How frequently this should be done varies based on the type of pessary, the amount of discharge that a woman produces, whether or not an odor develops after prolonged wearing of the pessary, and whether or not the patient’s vaginal mucosa has been abraded.

The question of timing for pessary cleaning

Although there are many opinions about how often pessaries should be removed and cleaned, no data in the literature support any specific interval. Pessaries that are easily removed by women themselves can be cleaned as frequently as desired, often on a weekly basis. The patient simply removes the pessary, washes it with soap and water, and reinserts it. For pessaries that are difficult to remove (such as the Gellhorn, cube, or donut) or for women who are physically unable to remove their own ring pessary, the clinician should remove and clean the pessary in the office every 3 to 6 months. It has been shown that there is no difference in complications from pessary use with either of these intervals.²

Prior to any vaginal surgical procedure, patients must be instructed to remove their pessary 10 to 14 days beforehand so that the surgeon can see the full extent of prolapse when making decisions about reconstruction and so that any vaginal mucosal erosions or abrasions have time to heal.

Office visits for follow-up care

The pessary “cleaning visit” has several goals, including to:

• see if the pessary is meeting the patient’s needs in terms of resolving symptoms of prolapse and/or restoring urinary continence
• discuss with the patient any problems she may be having, such as pelvic discomfort or pressure, difficulty voiding or defecating, excessive vaginal discharge, or vaginal odor
• check for vaginal mucosal erosion or ulceration; such vaginal lesions often can be prevented by the prophylactic use of either estrogen vaginal cream twice weekly or the continuous use of an estradiol vaginal ring in addition to the pessary
• evaluate the condition of the pessary itself and clean it with soap and water.

Continue to: Potential complications of pessary use...

The most common complications experienced by pessary users are:

Odor or excessive discharge. Bacterial vaginosis (BV) occurs more frequently in women who use pessaries. The symptoms of BV can be minimized—but unfortunately not totally eliminated—by the prophylactic use of antiseptic vaginal creams or gels, such as metronidazole, clindamycin, Trimo-San (oxyquinoline sulfate and sodium lauryl sulfate), and others. Inserting the gel vaginally once a week can significantly reduce discharge and odor.³

Vaginal mucosal erosion and ulceration. These are treated by removing the pessary for 2 weeks during which time estrogen cream is applied daily or an estradiol vaginal ring is put in place. If no resolution occurs after 2 weeks, the nonhealing vaginal mucosa should be biopsied.

Pressure on the rectum or bladder. If the pessary causes significant discomfort or interferes with voiding function, then either a different size or a different type pessary should be tried

Patients may discontinue pessary use for a variety of reasons. Among these are:

• discomfort
• inadequate improvement of POP or incontinence symptoms
• expulsion of the pessary during daily activities
• the patient’s desire for surgery instead
• worsening of urine leakage
• difficulty inserting or removing the pessary
• damage to the vaginal mucosa
• pain during removal of the pessary in the office.

Pessary effectiveness for POP and SUI symptoms

As might be expected with a device that is available in so many forms and is used to treat varied types of POP and SUI, the data concerning the success rates of pessary use vary considerably. These rates depend on the definition of success, that is, complete or partial control of prolapse and/or incontinence; which devices are being evaluated; and the nature and severity of the POP and/or SUI being treated.

That being said, a review of the literature reveals that the rates of prolapse symptom relief vary from 48% to 92% (TABLE 1).^4-13

As for success in relieving symptoms of incontinence, studies show improvements in from 40% to 77% of patients (TABLE 2).^6,8,14-17

In addition, some studies show a 50% improvement in bowel symptoms (urgency, obstruction, and anal incontinence) with the use of a pessary.^9,18

How pessaries compare with surgery

While surgery has the advantage of being a one-time fix with a very high rate of initial success in correcting both POP and incontinence, surgery also has potential drawbacks:

• It is an invasive procedure with the discomfort and risk of complications any surgery entails.
• There is a relatively high rate of prolapse recurrence.
• It exposes the patient to the possibility of mesh erosion if mesh is employed either for POP support or incontinence treatment.

Pessaries, on the other hand, are inexpensive, nonsurgical, removable, and allow for immediate correction of symptoms. Moreover, if the pessary is tried and is found to be unsatisfactory, surgery always can be performed subsequently.

Drawbacks of pessary treatment compared with surgery include the:

• ongoing need to wear an artificial internal device
• need for intermittent pessary removal and cleansing
• inability to have sexual intercourse with certain kinds of pessaries in place
• possible accumulation of vaginal discharge and odor.

Sexual activity and pessaries

Studies by Fernando, Meriwether, and Kuhn concur that for a substantial number of pessary users who are sexually active, both frequency and satisfaction with sexual intercourse are increased.^8,19,20 Kuhn further showed that desire, orgasm, and lubrication improved with the use of pessaries.²⁰ While some types of pessaries do require removal for intercourse, Clemons reported that issues involving sexual activity are not associated with pessary discontinuation.²¹

Using a pessary to predict a surgical outcome

Because a pessary elevates the pelvic organs, supports the vaginal walls, and lifts the bladder and urethra into a position that simulates the results of surgical repair, trial placement of a pessary can be used as a fairly accurate predictive tool to model what pelvic support and continence status will be after a proposed surgical procedure.^22,23 This is especially important because a significant number of patients with POP will have their occult stress incontinence unmasked following a reparative procedure.²⁴ A brief pessary trial prior to surgery, therefore, can be a useful tool for both patient and surgeon.

Continue to: Pessaries for prevention of preterm labor...

Pessaries for prevention of preterm labor

Almost 1 in 10 births in the United States occurs before 37 completed weeks of gestation.²⁵ Obstetricians have long thought that in women at risk for preterm delivery, the use of a pessary might help reduce the pressure of the growing uterus on the cervix and thus help prevent premature cervical dilation. It also has been thought that use of a pessary would be a safer and less invasive alternative to cervical cerclage. Many studies have evaluated the use of pessaries for the prevention of preterm labor with a mixture of positive (TABLE 3)^26-29 and negative results (TABLE 4).^30-33

From these data, it is reasonable to conclude that:

• The final answer concerning the effectiveness or lack thereof of pessary use in preventing preterm delivery is not yet in.
• Any advantage there might be to using pessaries to prevent preterm delivery cannot be too significant if multiple studies show as many negative outcomes as positive ones.

Pessary effectiveness in defecatory disorders

Vaginal birth has the potential to create multiple anatomic injuries in the anus, lower pelvis, and perineum that can affect defecation and bowel control. Tears of the anal sphincter, whether obvious or occult, may heal incompletely or be repaired inadequately.³⁴ Nerve innervation of the perianal and perineal areas can be interrupted or damaged by stretching, tearing, or prolonged compression. Of healthy parous adult women, 7% to 16% admit incontinence of gas or feces.^35,36

In addition, when a rectocele is present, stool in the lower rectum may cause bulging of the anterior rectal wall into the vagina, preventing stool from passing out of the anus. This sometimes requires women to digitally press their posterior vaginal walls during defecation to evacuate stool successfully. The question thus arises as to whether or not pessary placement and subsequent relief of rectoceles might facilitate bowel movements and decrease or eliminate defecatory dysfunction.

As with the issue of pessary use for prevention of preterm delivery, the answer is mixed. For instance, while Brazell¹⁸ showed that there was an overall improvement in bowel symptoms in pessary users, a study by Komesu¹⁰ did not demonstrate improvement.

There is, however, a relatively new device specifically designed to control defecatory problems: the vaginal bowel control system (Eclipse; Pelvalon). The silicon device is placed intravaginally as one does a pessary. After insertion, it is inflated via a valve and syringe. It works by putting pressure on and reversibly closing the lower rectum, thus blocking the uncontrolled passage of stool and gas. It can be worn continuously or intermittently, but it does need to be deflated for normal bowel movements. One trial of this device demonstrated a 50% reduction in incontinence episodes with a patient satisfaction rate of 84% at 3 months.³⁷ This device may well prove to be a valuable nonsurgical approach to the treatment of fecal incontinence. Unfortunately, the device is relatively expensive and usually is not covered by insurance as third-party payers do not consider it to be a pessary (which generally is covered).

Practice management particulars

Useful information on Current Procedural Terminology codes for pessaries, diagnostic codes, and the cost of various pessaries is provided in TABLE 5,³⁸TABLE 6,³⁹ and TABLE 7.^40-42

A contemporary device used since antiquity

Pessaries, considered “old-fashioned” by many gynecologists, are actually a very cost-effective and useful tool for the correction of POP and SUI. It behooves all who provide medical care to women to be familiar with them, to know when they might be useful, and to know how to fit and prescribe them. ●

CASE Unidentified ectopic pregnancy leads to rupture*

A 33-year-old woman (G1 P0010) with 2 positive home pregnancy tests presents to the emergency department (ED) reporting intermittent vaginal bleeding for 3 days. Her last menstrual period was 10 weeks ago, but she reports that her menses are always irregular. She has a history of asymptomatic chlamydia, as well as spontaneous abortion 2 years prior. At present, she denies abdominal pain or vaginal discharge.

Upon examination her vital signs are: temperature, 98.3 °F; pulse, 112 bpm, with a resting rate of 16 bpm; blood pressure (BP), 142/91 mm Hg; pulse O2, 99%; height, 4’ 3”; weight, 115 lb. Her labs are: hemoglobin, 12.1 g/dL; hematocrit, 38%; serum human chorionic gonadotropin (hCG) 236 mIU/mL. Upon pelvic examination, no active bleeding is noted. She agrees to be followed up by her gynecologist and is given a prescription for serum hCG in 2 days. She is instructed to return to the ED should she have pain or increased vaginal bleeding.

Three days later, the patient follows up with her gynecologist reporting mild cramping. She notes having had an episode of heavy vaginal bleeding and a “weakly positive” home pregnancy test. Transvaginal ultrasonography notes endometrial thickness 0.59 mm and unremarkable adnexa. A urine pregnancy test performed in the office is positive; urinalysis is positive for nitrites. With the bleeding slowed, the gynecologist’s overall impression is that the patient has undergone complete spontaneous abortion. She prescribes Macrobid for the urinary tract infection. She does not obtain the ED-prescribed serum HCG levels, as she feels, since complete spontaneous abortion has occurred there is no need to obtain a follow-up serum HCG.

Five days later, the patient returns to the ED reporting abdominal pain after eating. Fever and productive cough of 2 days are noted. The patient states that she had a recent miscarriage. The overall impression of the patient’s condition is bronchitis, and it is noted on the patient’s record, “unlikely ectopic pregnancy and pregnancy test may be false positive,” hence a pregnancy test is not ordered. Examination reveals mild suprapubic tenderness with no rebound; no pelvic exam is performed. The patient is instructed to follow up with a health care clinic within a week, and to return to the ED with severe abdominal pain, higher fever, or any new concerning symptoms. A Zithromax Z-pak is prescribed.

Four days later, the patient is brought by ambulance to the ED of the local major medical center with severe abdominal pain involving the right lower quadrant. She states that she had a miscarriage 3 weeks prior and was recently treated for bronchitis. She has dizziness when standing. Her vital signs are: temperature, 97.8 °F; heart rate, 95 bpm; BP, 72/48 mm Hg; pulse O2, 100%. She reports her abdominal pain to be 6/10.

The patient is given a Lactated Ringer’s bolus of 1,000 mL for a hypotensive episode. Computed tomography is obtained and notes, “low attenuation in the left adnexa with a dilated fallopian tube.” A large heterogeneous collection of fluid in the pelvis is noted with active extravasation, consistent with an “acute bleed.”

The patient is brought to the operating room with a diagnosis of probable ruptured ectopic pregnancy. Intraoperatively she is noted to have a right ruptured ectopic and left tubo-ovarian abscess. The surgeon proceeds with right salpingectomy and left salpingo-oophorectomy. Three liters of hemoperitoneum is found.

She is followed postoperatively with serum hCG until levels are negative. Her postoperative course is uneventful. Her only future option for pregnancy is through assisted reproductive technology (ART) with in vitro fertilization (IVF). The patient sues the gynecologist and second ED physician for presumed inappropriate assessment for ectopic pregnancy.

*The “facts” of this case are a composite, drawn from several cases to illustrate medical and legal issues. The statement of facts should be considered hypothetical.

Continue to: WHAT’S THE VERDICT?...

WHAT’S THE VERDICT?

A defense verdict is returned.

Medical considerations

The incidence of ectopic pregnancy is 2% of all pregnancies, with a higher incidence (about 4%) among infertility patients.¹ Up to 10% of ectopic pregnancies have no symptoms.²

Clinical presentations. Classic signs of ectopic pregnancy include:

• abdominal pain
• vaginal bleeding
• late menses (often noted).

A recent case of ectopic pregnancy presenting with chest pain was reported.³ Clinicians must never lose site of the fact that ectopic pregnancy is the most common cause of maternal mortality in the first trimester, with an incidence of 1% to 10% of all first-trimester deaths.⁴

Risk factors include pelvic inflammatory disease, as demonstrated in the opening case. “The silent epidemic of chlamydia” comes to mind, and tobacco smoking can adversely affect tubal cilia, as can pelvic adhesions and/or prior tubal surgery. All of these factors can predispose a patient to ectopic pregnancy; in addition, intrauterine devices, endometriosis, tubal ligation (or ligation reversal), all can set the stage for an ectopic pregnancy.⁵ Appropriate serum hCG monitoring during early pregnancy can assist in sorting out pregnancies of unknown location (PUL; FIGURE). First trimester ultrasonography, at 5 weeks gestation, usually identifies early intrauterine gestation.

Heterotopic pregnancy includes an intrauterine gestation and an ectopic pregnancy. This presentation includes the presence of a “pseudosac” in the endometrial cavity plus an extrauterine gestation. Heterotopic pregnancies have become somewhat more common as ART/IVF has unfolded, especially prior to the predominance of single embryo transfer.

Managing ectopic pregnancy

For cases of early pregnancy complicated by intermittent bleeding and/or pain, monitoring with serum hCG levels at 48-hour intervals to distinguish a viable IUP from an abnormal IUP or an ectopic is appropriate. The “discriminatory zone” collates serum hCG levels with findings on ultrasonography. Specific lower limits of serum hCG levels are not clear cut, with recommendations of 3,500 mIU/mL to provide sonographic evidence of an intrauterine gestation “to avoid misdiagnosis and possible interruption of intrauterine pregnancy,” as conveyed in the American College of Obstetricians and Gynecologists 2018 practice bulletin.⁸ Serum progesterone levels also have been suggested to complement hCG levels; a progesterone level of <20 nmol/L is consistent with an abnormal pregnancy, whereas levels >25 nmol/L are suggestive of a viable pregnancy.² Inhibin A levels also have been suggested to be helpful, but they are not an ideal monitoring tool.

While most ectopic pregnancies are located in the fallopian tube, other locations also can be abdominal or ovarian. In addition, cesarean scar ectopic pregnancy can occur and often is associated with delay in diagnosis and greater morbidity due to such delay.⁹ With regard to ovarian ectopic, Spiegelberg criteria are established for diagnosis (TABLE 1).¹⁰

Appropriate management of an ectopic pregnancy is dependent upon the gestational age, serum hCG levels, and imaging findings, as well as the patient’s symptoms and exam findings. Treatment is established in large part on a case-by-case basis and includes, for early pregnancy, expectant management and use of methotrexate (TABLE 2).¹¹ Dilation and curettage may be used to identify the pregnancy’s location when the serum hCG level is below 2,000 mIU/mL and there is no evidence of an IUP on ultrasound. Surgical treatment can include minimally invasive salpingostomy or salpingectomy and, depending on circumstance, laparotomy may be indicated.

Continue to: Legal perspective...

Legal perspective

Lawsuits related to ectopic pregnancy are not a new phenomenon. In fact, in 1897, a physician in Ohio who misdiagnosed an “extrauterine pregnancy” as appendicitis was the center of a malpractice lawsuit.¹³ Unrecognized or mishandled ectopic pregnancy can result in serious injuries—in the range of 1% to 10% (see above) of maternal deaths are related to ectopic pregnancy.¹⁴ Ectopic pregnancy cases, therefore, have been the subject of substantial litigation over the years. An informal, noncomprehensive review of malpractice lawsuits brought from 2000 to 2019, found more than 300 ectopic pregnancy cases. Given the large number of malpractice claims against ObGyns,¹⁵ ectopic pregnancy cases are only a small portion of all ObGyn malpractice cases.¹⁶

A common claim: negligent diagnosis or treatment

The most common basis for lawsuits in cases of ectopic pregnancy is the clinician’s negligent failure to properly diagnose the ectopic nature of the pregnancy. There are also a number of cases claiming negligent treatment of an identified ectopic pregnancy. Not every missed diagnosis, or unsuccessful treatment, leads to liability, of course. It is only when a diagnosis or treatment fails to meet the standard of care within the profession that there should be liability. That standard of care is generally defined by what a reasonably prudent physician would do under the circumstances. Expert witnesses, who are familiar with the standard of practice within the specialty, are usually necessary to establish what that practice is. Both the plaintiff and the defense obtain experts, the former to prove what the standard of care is and that the standard was not met in the case at hand. The defense experts are usually arguing that the standard of care was met.¹⁷ Inadequate diagnosis of ectopic pregnancy or other condition may arise from a failure to take a sufficient history, conduct an appropriately thorough physical examination, recognize any of the symptoms that would suggest it is present, use and conduct ultrasound correctly, or follow-up appropriately with additional testing.¹⁸

A malpractice claim of negligent treatment can involve any the following circumstances¹⁹:

• failure to establish an appropriate treatment plan
• prescribing inappropriate medications for the patient (eg, methotrexate, when it is contraindicated)
• delivering the wrong medication or the wrong amount of the right medication
• performing a procedure badly
• undertaking a new treatment without adequate instruction and preparation.

Given the nature and risks of ectopic pregnancy, ongoing, frequent contact with the patient is essential from the point at which the condition is suspected. The greater the risk of harm (probability or consequence), the more careful any professional ought to be. Because ectopic pregnancy is not an uncommon occurrence, and because it can have devastating effects, including death, a reasonably prudent practitioner would be especially aware of the clinical presentations discussed above.²⁰ In the opening case, the treatment plan was not well documented.

Negligence must lead to patient harm. In addition to negligence (proving that the physician did not act in accordance with the standard of care), to prevail in a malpractice case, the plaintiff-patient must prove that the negligence caused the injury, or worsened it. If the failure to make a diagnosis would not have made any difference in a harm the patient suffered, there are no damages and no liability. Suppose, for example, that a physician negligently failed to diagnose ectopic pregnancy, but performed surgery expecting to find the misdiagnosed condition. In the course of the surgery, however, the surgeon discovered and appropriately treated the ectopic pregnancy. (A version of this happened in the old 19th century case mentioned above.) The negligence of the physician did not cause harm, so there are no damages and no liability.

Continue to: Informed consent is vital...

Informed consent is vital

A part of malpractice is informed consent (or the absence of it)—issues that can arise in any medical care.²¹ It is wise to pay particular attention in cases where the nature of the illness is unknown, and where there are significant uncertainties and the nature of testing and treatment may change substantially over a period of a few days or few weeks. As always, informed consent should include a discussion of what process or procedure is proposed, its risks and benefits, alternative approaches that might be available, and the risk of doing nothing. Frequently, the uncertainty of ectopic pregnancy complicates the informed consent process.²²

Because communication with the patient is an essential function of informed consent, the consent process should productively be used in PUL and similar cases to inform the patient about the uncertainty, and the testing and (nonsurgical) treatment that will occur. This is an opportunity to reinforce the message that the patient must maintain ongoing communication with the physician’s office about changes in her condition, and appear for each appointment scheduled. If more invasive procedures—notably surgery—become required, a separate consent process should be completed, because the risks and considerations are now meaningfully different than when treatment began. As a general matter, any possible treatment that may result in infertility or reduced reproductive capacity should specifically be included in the consent process.

In the hypothetical case, the gynecologist failed to obtain a follow-up serum hCG level. In addition, the record did not reflect ectopic pregnancy in the differential diagnosis. As noted above, the patient had predisposing factors for an ectopic pregnancy. The physician should have acknowledged the history of sexually transmitted disease predisposing her to an ectopic pregnancy. Monitoring of serum hCG levels until they are negative is appropriate with ectopic, or presumed ectopic, pregnancy management. Appropriate monitoring did not occur in this case. Each of these errors (following up on serum hCG levels and the inadequacy of notations about the possibility of ectopic pregnancy) seem inconsistent with the usual standard of care. Furthermore, as a result of the outcome, the only future option for the patient to pursue pregnancy was IVF.

Other legal issues

There are a number of other legal issues that are associated with the topic of ectopic pregnancy. There is evidence, for example, that Catholic and non-Catholic hospitals treat ectopic pregnancies differently,²³ which may reflect different views on taking a life or the use of methotrexate and its association with abortion.²⁴ In addition, the possibility of an increase in future ectopic pregnancies is one of the “risks” of abortion that pro-life organizations have pushed to see included in abortion informed consent.²⁵ This has led some commentators to conclude that some Catholic hospitals violate federal law in managing ectopic pregnancy. There is also evidence of “overwhelming rates of medical misinformation on pregnancy center websites, including a link between abortion and ectopic pregnancy.”²⁶

The fact that cesarean deliveries are related to an increased risk for ectopic pregnancy (because of the risk of cesarean scar ectopic pregnancy) also has been cited as information that should play a role in the consent process for cesarean delivery.²⁷ In terms of liability, failed tubal ligation leads to a 33% risk of ectopic pregnancy.²⁸ The risk of ectopic pregnancy is also commonly included in surrogacy contracts.²⁹

Why the outcome was for the defense

The opening hypothetical case illustrates some of the uncertainties of medical malpractice cases. As noted, there appeared a deviation from the usual standard of care, particularly the failure to follow up on the serum hCG level. The weakness in the medical record, failing to note the possibility of ectopic pregnancy, also was probably an error but, apparently, the court felt that this did not result in any harm to the patient.

The question arises of how there would be a defense verdict in light of the failure to track consecutive serum hCG levels. A speculative explanation is that there are many uncertainties in most lawsuits. Procedural problems may result in a case being limited, expert witnesses are essential to both the plaintiff and defense, with the quality of their review and testimony possibly uneven. Judges and juries may rely on one expert witness rather than another, juries vary, and the quality of advocacy differs. Any of these situations can contribute to the unpredictability of the outcome of a case. In the case above, the liability was somewhat uncertain, and the various other factors tipped in favor of a defense verdict. ●

CASE Unidentified ectopic pregnancy leads to rupture*

A 33-year-old woman (G1 P0010) with 2 positive home pregnancy tests presents to the emergency department (ED) reporting intermittent vaginal bleeding for 3 days. Her last menstrual period was 10 weeks ago, but she reports that her menses are always irregular. She has a history of asymptomatic chlamydia, as well as spontaneous abortion 2 years prior. At present, she denies abdominal pain or vaginal discharge.

Upon examination her vital signs are: temperature, 98.3 °F; pulse, 112 bpm, with a resting rate of 16 bpm; blood pressure (BP), 142/91 mm Hg; pulse O2, 99%; height, 4’ 3”; weight, 115 lb. Her labs are: hemoglobin, 12.1 g/dL; hematocrit, 38%; serum human chorionic gonadotropin (hCG) 236 mIU/mL. Upon pelvic examination, no active bleeding is noted. She agrees to be followed up by her gynecologist and is given a prescription for serum hCG in 2 days. She is instructed to return to the ED should she have pain or increased vaginal bleeding.

Three days later, the patient follows up with her gynecologist reporting mild cramping. She notes having had an episode of heavy vaginal bleeding and a “weakly positive” home pregnancy test. Transvaginal ultrasonography notes endometrial thickness 0.59 mm and unremarkable adnexa. A urine pregnancy test performed in the office is positive; urinalysis is positive for nitrites. With the bleeding slowed, the gynecologist’s overall impression is that the patient has undergone complete spontaneous abortion. She prescribes Macrobid for the urinary tract infection. She does not obtain the ED-prescribed serum HCG levels, as she feels, since complete spontaneous abortion has occurred there is no need to obtain a follow-up serum HCG.

Five days later, the patient returns to the ED reporting abdominal pain after eating. Fever and productive cough of 2 days are noted. The patient states that she had a recent miscarriage. The overall impression of the patient’s condition is bronchitis, and it is noted on the patient’s record, “unlikely ectopic pregnancy and pregnancy test may be false positive,” hence a pregnancy test is not ordered. Examination reveals mild suprapubic tenderness with no rebound; no pelvic exam is performed. The patient is instructed to follow up with a health care clinic within a week, and to return to the ED with severe abdominal pain, higher fever, or any new concerning symptoms. A Zithromax Z-pak is prescribed.

Four days later, the patient is brought by ambulance to the ED of the local major medical center with severe abdominal pain involving the right lower quadrant. She states that she had a miscarriage 3 weeks prior and was recently treated for bronchitis. She has dizziness when standing. Her vital signs are: temperature, 97.8 °F; heart rate, 95 bpm; BP, 72/48 mm Hg; pulse O2, 100%. She reports her abdominal pain to be 6/10.

The patient is given a Lactated Ringer’s bolus of 1,000 mL for a hypotensive episode. Computed tomography is obtained and notes, “low attenuation in the left adnexa with a dilated fallopian tube.” A large heterogeneous collection of fluid in the pelvis is noted with active extravasation, consistent with an “acute bleed.”

The patient is brought to the operating room with a diagnosis of probable ruptured ectopic pregnancy. Intraoperatively she is noted to have a right ruptured ectopic and left tubo-ovarian abscess. The surgeon proceeds with right salpingectomy and left salpingo-oophorectomy. Three liters of hemoperitoneum is found.

She is followed postoperatively with serum hCG until levels are negative. Her postoperative course is uneventful. Her only future option for pregnancy is through assisted reproductive technology (ART) with in vitro fertilization (IVF). The patient sues the gynecologist and second ED physician for presumed inappropriate assessment for ectopic pregnancy.

*The “facts” of this case are a composite, drawn from several cases to illustrate medical and legal issues. The statement of facts should be considered hypothetical.

Continue to: WHAT’S THE VERDICT?...

WHAT’S THE VERDICT?

A defense verdict is returned.

Medical considerations

The incidence of ectopic pregnancy is 2% of all pregnancies, with a higher incidence (about 4%) among infertility patients.¹ Up to 10% of ectopic pregnancies have no symptoms.²

Clinical presentations. Classic signs of ectopic pregnancy include:

• abdominal pain
• vaginal bleeding
• late menses (often noted).

A recent case of ectopic pregnancy presenting with chest pain was reported.³ Clinicians must never lose site of the fact that ectopic pregnancy is the most common cause of maternal mortality in the first trimester, with an incidence of 1% to 10% of all first-trimester deaths.⁴

Risk factors include pelvic inflammatory disease, as demonstrated in the opening case. “The silent epidemic of chlamydia” comes to mind, and tobacco smoking can adversely affect tubal cilia, as can pelvic adhesions and/or prior tubal surgery. All of these factors can predispose a patient to ectopic pregnancy; in addition, intrauterine devices, endometriosis, tubal ligation (or ligation reversal), all can set the stage for an ectopic pregnancy.⁵ Appropriate serum hCG monitoring during early pregnancy can assist in sorting out pregnancies of unknown location (PUL; FIGURE). First trimester ultrasonography, at 5 weeks gestation, usually identifies early intrauterine gestation.

Heterotopic pregnancy includes an intrauterine gestation and an ectopic pregnancy. This presentation includes the presence of a “pseudosac” in the endometrial cavity plus an extrauterine gestation. Heterotopic pregnancies have become somewhat more common as ART/IVF has unfolded, especially prior to the predominance of single embryo transfer.

Managing ectopic pregnancy

For cases of early pregnancy complicated by intermittent bleeding and/or pain, monitoring with serum hCG levels at 48-hour intervals to distinguish a viable IUP from an abnormal IUP or an ectopic is appropriate. The “discriminatory zone” collates serum hCG levels with findings on ultrasonography. Specific lower limits of serum hCG levels are not clear cut, with recommendations of 3,500 mIU/mL to provide sonographic evidence of an intrauterine gestation “to avoid misdiagnosis and possible interruption of intrauterine pregnancy,” as conveyed in the American College of Obstetricians and Gynecologists 2018 practice bulletin.⁸ Serum progesterone levels also have been suggested to complement hCG levels; a progesterone level of <20 nmol/L is consistent with an abnormal pregnancy, whereas levels >25 nmol/L are suggestive of a viable pregnancy.² Inhibin A levels also have been suggested to be helpful, but they are not an ideal monitoring tool.

While most ectopic pregnancies are located in the fallopian tube, other locations also can be abdominal or ovarian. In addition, cesarean scar ectopic pregnancy can occur and often is associated with delay in diagnosis and greater morbidity due to such delay.⁹ With regard to ovarian ectopic, Spiegelberg criteria are established for diagnosis (TABLE 1).¹⁰

Appropriate management of an ectopic pregnancy is dependent upon the gestational age, serum hCG levels, and imaging findings, as well as the patient’s symptoms and exam findings. Treatment is established in large part on a case-by-case basis and includes, for early pregnancy, expectant management and use of methotrexate (TABLE 2).¹¹ Dilation and curettage may be used to identify the pregnancy’s location when the serum hCG level is below 2,000 mIU/mL and there is no evidence of an IUP on ultrasound. Surgical treatment can include minimally invasive salpingostomy or salpingectomy and, depending on circumstance, laparotomy may be indicated.

Continue to: Legal perspective...

Legal perspective

Lawsuits related to ectopic pregnancy are not a new phenomenon. In fact, in 1897, a physician in Ohio who misdiagnosed an “extrauterine pregnancy” as appendicitis was the center of a malpractice lawsuit.¹³ Unrecognized or mishandled ectopic pregnancy can result in serious injuries—in the range of 1% to 10% (see above) of maternal deaths are related to ectopic pregnancy.¹⁴ Ectopic pregnancy cases, therefore, have been the subject of substantial litigation over the years. An informal, noncomprehensive review of malpractice lawsuits brought from 2000 to 2019, found more than 300 ectopic pregnancy cases. Given the large number of malpractice claims against ObGyns,¹⁵ ectopic pregnancy cases are only a small portion of all ObGyn malpractice cases.¹⁶

A common claim: negligent diagnosis or treatment

The most common basis for lawsuits in cases of ectopic pregnancy is the clinician’s negligent failure to properly diagnose the ectopic nature of the pregnancy. There are also a number of cases claiming negligent treatment of an identified ectopic pregnancy. Not every missed diagnosis, or unsuccessful treatment, leads to liability, of course. It is only when a diagnosis or treatment fails to meet the standard of care within the profession that there should be liability. That standard of care is generally defined by what a reasonably prudent physician would do under the circumstances. Expert witnesses, who are familiar with the standard of practice within the specialty, are usually necessary to establish what that practice is. Both the plaintiff and the defense obtain experts, the former to prove what the standard of care is and that the standard was not met in the case at hand. The defense experts are usually arguing that the standard of care was met.¹⁷ Inadequate diagnosis of ectopic pregnancy or other condition may arise from a failure to take a sufficient history, conduct an appropriately thorough physical examination, recognize any of the symptoms that would suggest it is present, use and conduct ultrasound correctly, or follow-up appropriately with additional testing.¹⁸

A malpractice claim of negligent treatment can involve any the following circumstances¹⁹:

• failure to establish an appropriate treatment plan
• prescribing inappropriate medications for the patient (eg, methotrexate, when it is contraindicated)
• delivering the wrong medication or the wrong amount of the right medication
• performing a procedure badly
• undertaking a new treatment without adequate instruction and preparation.

Given the nature and risks of ectopic pregnancy, ongoing, frequent contact with the patient is essential from the point at which the condition is suspected. The greater the risk of harm (probability or consequence), the more careful any professional ought to be. Because ectopic pregnancy is not an uncommon occurrence, and because it can have devastating effects, including death, a reasonably prudent practitioner would be especially aware of the clinical presentations discussed above.²⁰ In the opening case, the treatment plan was not well documented.

Negligence must lead to patient harm. In addition to negligence (proving that the physician did not act in accordance with the standard of care), to prevail in a malpractice case, the plaintiff-patient must prove that the negligence caused the injury, or worsened it. If the failure to make a diagnosis would not have made any difference in a harm the patient suffered, there are no damages and no liability. Suppose, for example, that a physician negligently failed to diagnose ectopic pregnancy, but performed surgery expecting to find the misdiagnosed condition. In the course of the surgery, however, the surgeon discovered and appropriately treated the ectopic pregnancy. (A version of this happened in the old 19th century case mentioned above.) The negligence of the physician did not cause harm, so there are no damages and no liability.

Continue to: Informed consent is vital...

Informed consent is vital

A part of malpractice is informed consent (or the absence of it)—issues that can arise in any medical care.²¹ It is wise to pay particular attention in cases where the nature of the illness is unknown, and where there are significant uncertainties and the nature of testing and treatment may change substantially over a period of a few days or few weeks. As always, informed consent should include a discussion of what process or procedure is proposed, its risks and benefits, alternative approaches that might be available, and the risk of doing nothing. Frequently, the uncertainty of ectopic pregnancy complicates the informed consent process.²²

Because communication with the patient is an essential function of informed consent, the consent process should productively be used in PUL and similar cases to inform the patient about the uncertainty, and the testing and (nonsurgical) treatment that will occur. This is an opportunity to reinforce the message that the patient must maintain ongoing communication with the physician’s office about changes in her condition, and appear for each appointment scheduled. If more invasive procedures—notably surgery—become required, a separate consent process should be completed, because the risks and considerations are now meaningfully different than when treatment began. As a general matter, any possible treatment that may result in infertility or reduced reproductive capacity should specifically be included in the consent process.

In the hypothetical case, the gynecologist failed to obtain a follow-up serum hCG level. In addition, the record did not reflect ectopic pregnancy in the differential diagnosis. As noted above, the patient had predisposing factors for an ectopic pregnancy. The physician should have acknowledged the history of sexually transmitted disease predisposing her to an ectopic pregnancy. Monitoring of serum hCG levels until they are negative is appropriate with ectopic, or presumed ectopic, pregnancy management. Appropriate monitoring did not occur in this case. Each of these errors (following up on serum hCG levels and the inadequacy of notations about the possibility of ectopic pregnancy) seem inconsistent with the usual standard of care. Furthermore, as a result of the outcome, the only future option for the patient to pursue pregnancy was IVF.

Other legal issues

There are a number of other legal issues that are associated with the topic of ectopic pregnancy. There is evidence, for example, that Catholic and non-Catholic hospitals treat ectopic pregnancies differently,²³ which may reflect different views on taking a life or the use of methotrexate and its association with abortion.²⁴ In addition, the possibility of an increase in future ectopic pregnancies is one of the “risks” of abortion that pro-life organizations have pushed to see included in abortion informed consent.²⁵ This has led some commentators to conclude that some Catholic hospitals violate federal law in managing ectopic pregnancy. There is also evidence of “overwhelming rates of medical misinformation on pregnancy center websites, including a link between abortion and ectopic pregnancy.”²⁶

The fact that cesarean deliveries are related to an increased risk for ectopic pregnancy (because of the risk of cesarean scar ectopic pregnancy) also has been cited as information that should play a role in the consent process for cesarean delivery.²⁷ In terms of liability, failed tubal ligation leads to a 33% risk of ectopic pregnancy.²⁸ The risk of ectopic pregnancy is also commonly included in surrogacy contracts.²⁹

Why the outcome was for the defense

The opening hypothetical case illustrates some of the uncertainties of medical malpractice cases. As noted, there appeared a deviation from the usual standard of care, particularly the failure to follow up on the serum hCG level. The weakness in the medical record, failing to note the possibility of ectopic pregnancy, also was probably an error but, apparently, the court felt that this did not result in any harm to the patient.

The question arises of how there would be a defense verdict in light of the failure to track consecutive serum hCG levels. A speculative explanation is that there are many uncertainties in most lawsuits. Procedural problems may result in a case being limited, expert witnesses are essential to both the plaintiff and defense, with the quality of their review and testimony possibly uneven. Judges and juries may rely on one expert witness rather than another, juries vary, and the quality of advocacy differs. Any of these situations can contribute to the unpredictability of the outcome of a case. In the case above, the liability was somewhat uncertain, and the various other factors tipped in favor of a defense verdict. ●

CASE Unidentified ectopic pregnancy leads to rupture*

A 33-year-old woman (G1 P0010) with 2 positive home pregnancy tests presents to the emergency department (ED) reporting intermittent vaginal bleeding for 3 days. Her last menstrual period was 10 weeks ago, but she reports that her menses are always irregular. She has a history of asymptomatic chlamydia, as well as spontaneous abortion 2 years prior. At present, she denies abdominal pain or vaginal discharge.

Upon examination her vital signs are: temperature, 98.3 °F; pulse, 112 bpm, with a resting rate of 16 bpm; blood pressure (BP), 142/91 mm Hg; pulse O2, 99%; height, 4’ 3”; weight, 115 lb. Her labs are: hemoglobin, 12.1 g/dL; hematocrit, 38%; serum human chorionic gonadotropin (hCG) 236 mIU/mL. Upon pelvic examination, no active bleeding is noted. She agrees to be followed up by her gynecologist and is given a prescription for serum hCG in 2 days. She is instructed to return to the ED should she have pain or increased vaginal bleeding.

Three days later, the patient follows up with her gynecologist reporting mild cramping. She notes having had an episode of heavy vaginal bleeding and a “weakly positive” home pregnancy test. Transvaginal ultrasonography notes endometrial thickness 0.59 mm and unremarkable adnexa. A urine pregnancy test performed in the office is positive; urinalysis is positive for nitrites. With the bleeding slowed, the gynecologist’s overall impression is that the patient has undergone complete spontaneous abortion. She prescribes Macrobid for the urinary tract infection. She does not obtain the ED-prescribed serum HCG levels, as she feels, since complete spontaneous abortion has occurred there is no need to obtain a follow-up serum HCG.

Five days later, the patient returns to the ED reporting abdominal pain after eating. Fever and productive cough of 2 days are noted. The patient states that she had a recent miscarriage. The overall impression of the patient’s condition is bronchitis, and it is noted on the patient’s record, “unlikely ectopic pregnancy and pregnancy test may be false positive,” hence a pregnancy test is not ordered. Examination reveals mild suprapubic tenderness with no rebound; no pelvic exam is performed. The patient is instructed to follow up with a health care clinic within a week, and to return to the ED with severe abdominal pain, higher fever, or any new concerning symptoms. A Zithromax Z-pak is prescribed.

Four days later, the patient is brought by ambulance to the ED of the local major medical center with severe abdominal pain involving the right lower quadrant. She states that she had a miscarriage 3 weeks prior and was recently treated for bronchitis. She has dizziness when standing. Her vital signs are: temperature, 97.8 °F; heart rate, 95 bpm; BP, 72/48 mm Hg; pulse O2, 100%. She reports her abdominal pain to be 6/10.

The patient is given a Lactated Ringer’s bolus of 1,000 mL for a hypotensive episode. Computed tomography is obtained and notes, “low attenuation in the left adnexa with a dilated fallopian tube.” A large heterogeneous collection of fluid in the pelvis is noted with active extravasation, consistent with an “acute bleed.”

The patient is brought to the operating room with a diagnosis of probable ruptured ectopic pregnancy. Intraoperatively she is noted to have a right ruptured ectopic and left tubo-ovarian abscess. The surgeon proceeds with right salpingectomy and left salpingo-oophorectomy. Three liters of hemoperitoneum is found.

She is followed postoperatively with serum hCG until levels are negative. Her postoperative course is uneventful. Her only future option for pregnancy is through assisted reproductive technology (ART) with in vitro fertilization (IVF). The patient sues the gynecologist and second ED physician for presumed inappropriate assessment for ectopic pregnancy.

*The “facts” of this case are a composite, drawn from several cases to illustrate medical and legal issues. The statement of facts should be considered hypothetical.

Continue to: WHAT’S THE VERDICT?...

WHAT’S THE VERDICT?

A defense verdict is returned.

Medical considerations

The incidence of ectopic pregnancy is 2% of all pregnancies, with a higher incidence (about 4%) among infertility patients.¹ Up to 10% of ectopic pregnancies have no symptoms.²

Clinical presentations. Classic signs of ectopic pregnancy include:

• abdominal pain
• vaginal bleeding
• late menses (often noted).

A recent case of ectopic pregnancy presenting with chest pain was reported.³ Clinicians must never lose site of the fact that ectopic pregnancy is the most common cause of maternal mortality in the first trimester, with an incidence of 1% to 10% of all first-trimester deaths.⁴

Risk factors include pelvic inflammatory disease, as demonstrated in the opening case. “The silent epidemic of chlamydia” comes to mind, and tobacco smoking can adversely affect tubal cilia, as can pelvic adhesions and/or prior tubal surgery. All of these factors can predispose a patient to ectopic pregnancy; in addition, intrauterine devices, endometriosis, tubal ligation (or ligation reversal), all can set the stage for an ectopic pregnancy.⁵ Appropriate serum hCG monitoring during early pregnancy can assist in sorting out pregnancies of unknown location (PUL; FIGURE). First trimester ultrasonography, at 5 weeks gestation, usually identifies early intrauterine gestation.

Heterotopic pregnancy includes an intrauterine gestation and an ectopic pregnancy. This presentation includes the presence of a “pseudosac” in the endometrial cavity plus an extrauterine gestation. Heterotopic pregnancies have become somewhat more common as ART/IVF has unfolded, especially prior to the predominance of single embryo transfer.

Managing ectopic pregnancy

For cases of early pregnancy complicated by intermittent bleeding and/or pain, monitoring with serum hCG levels at 48-hour intervals to distinguish a viable IUP from an abnormal IUP or an ectopic is appropriate. The “discriminatory zone” collates serum hCG levels with findings on ultrasonography. Specific lower limits of serum hCG levels are not clear cut, with recommendations of 3,500 mIU/mL to provide sonographic evidence of an intrauterine gestation “to avoid misdiagnosis and possible interruption of intrauterine pregnancy,” as conveyed in the American College of Obstetricians and Gynecologists 2018 practice bulletin.⁸ Serum progesterone levels also have been suggested to complement hCG levels; a progesterone level of <20 nmol/L is consistent with an abnormal pregnancy, whereas levels >25 nmol/L are suggestive of a viable pregnancy.² Inhibin A levels also have been suggested to be helpful, but they are not an ideal monitoring tool.

While most ectopic pregnancies are located in the fallopian tube, other locations also can be abdominal or ovarian. In addition, cesarean scar ectopic pregnancy can occur and often is associated with delay in diagnosis and greater morbidity due to such delay.⁹ With regard to ovarian ectopic, Spiegelberg criteria are established for diagnosis (TABLE 1).¹⁰

Appropriate management of an ectopic pregnancy is dependent upon the gestational age, serum hCG levels, and imaging findings, as well as the patient’s symptoms and exam findings. Treatment is established in large part on a case-by-case basis and includes, for early pregnancy, expectant management and use of methotrexate (TABLE 2).¹¹ Dilation and curettage may be used to identify the pregnancy’s location when the serum hCG level is below 2,000 mIU/mL and there is no evidence of an IUP on ultrasound. Surgical treatment can include minimally invasive salpingostomy or salpingectomy and, depending on circumstance, laparotomy may be indicated.

Continue to: Legal perspective...

Legal perspective

Lawsuits related to ectopic pregnancy are not a new phenomenon. In fact, in 1897, a physician in Ohio who misdiagnosed an “extrauterine pregnancy” as appendicitis was the center of a malpractice lawsuit.¹³ Unrecognized or mishandled ectopic pregnancy can result in serious injuries—in the range of 1% to 10% (see above) of maternal deaths are related to ectopic pregnancy.¹⁴ Ectopic pregnancy cases, therefore, have been the subject of substantial litigation over the years. An informal, noncomprehensive review of malpractice lawsuits brought from 2000 to 2019, found more than 300 ectopic pregnancy cases. Given the large number of malpractice claims against ObGyns,¹⁵ ectopic pregnancy cases are only a small portion of all ObGyn malpractice cases.¹⁶

A common claim: negligent diagnosis or treatment

The most common basis for lawsuits in cases of ectopic pregnancy is the clinician’s negligent failure to properly diagnose the ectopic nature of the pregnancy. There are also a number of cases claiming negligent treatment of an identified ectopic pregnancy. Not every missed diagnosis, or unsuccessful treatment, leads to liability, of course. It is only when a diagnosis or treatment fails to meet the standard of care within the profession that there should be liability. That standard of care is generally defined by what a reasonably prudent physician would do under the circumstances. Expert witnesses, who are familiar with the standard of practice within the specialty, are usually necessary to establish what that practice is. Both the plaintiff and the defense obtain experts, the former to prove what the standard of care is and that the standard was not met in the case at hand. The defense experts are usually arguing that the standard of care was met.¹⁷ Inadequate diagnosis of ectopic pregnancy or other condition may arise from a failure to take a sufficient history, conduct an appropriately thorough physical examination, recognize any of the symptoms that would suggest it is present, use and conduct ultrasound correctly, or follow-up appropriately with additional testing.¹⁸

A malpractice claim of negligent treatment can involve any the following circumstances¹⁹:

• failure to establish an appropriate treatment plan
• prescribing inappropriate medications for the patient (eg, methotrexate, when it is contraindicated)
• delivering the wrong medication or the wrong amount of the right medication
• performing a procedure badly
• undertaking a new treatment without adequate instruction and preparation.

Given the nature and risks of ectopic pregnancy, ongoing, frequent contact with the patient is essential from the point at which the condition is suspected. The greater the risk of harm (probability or consequence), the more careful any professional ought to be. Because ectopic pregnancy is not an uncommon occurrence, and because it can have devastating effects, including death, a reasonably prudent practitioner would be especially aware of the clinical presentations discussed above.²⁰ In the opening case, the treatment plan was not well documented.

Negligence must lead to patient harm. In addition to negligence (proving that the physician did not act in accordance with the standard of care), to prevail in a malpractice case, the plaintiff-patient must prove that the negligence caused the injury, or worsened it. If the failure to make a diagnosis would not have made any difference in a harm the patient suffered, there are no damages and no liability. Suppose, for example, that a physician negligently failed to diagnose ectopic pregnancy, but performed surgery expecting to find the misdiagnosed condition. In the course of the surgery, however, the surgeon discovered and appropriately treated the ectopic pregnancy. (A version of this happened in the old 19th century case mentioned above.) The negligence of the physician did not cause harm, so there are no damages and no liability.

Continue to: Informed consent is vital...

Informed consent is vital

A part of malpractice is informed consent (or the absence of it)—issues that can arise in any medical care.²¹ It is wise to pay particular attention in cases where the nature of the illness is unknown, and where there are significant uncertainties and the nature of testing and treatment may change substantially over a period of a few days or few weeks. As always, informed consent should include a discussion of what process or procedure is proposed, its risks and benefits, alternative approaches that might be available, and the risk of doing nothing. Frequently, the uncertainty of ectopic pregnancy complicates the informed consent process.²²

Because communication with the patient is an essential function of informed consent, the consent process should productively be used in PUL and similar cases to inform the patient about the uncertainty, and the testing and (nonsurgical) treatment that will occur. This is an opportunity to reinforce the message that the patient must maintain ongoing communication with the physician’s office about changes in her condition, and appear for each appointment scheduled. If more invasive procedures—notably surgery—become required, a separate consent process should be completed, because the risks and considerations are now meaningfully different than when treatment began. As a general matter, any possible treatment that may result in infertility or reduced reproductive capacity should specifically be included in the consent process.

In the hypothetical case, the gynecologist failed to obtain a follow-up serum hCG level. In addition, the record did not reflect ectopic pregnancy in the differential diagnosis. As noted above, the patient had predisposing factors for an ectopic pregnancy. The physician should have acknowledged the history of sexually transmitted disease predisposing her to an ectopic pregnancy. Monitoring of serum hCG levels until they are negative is appropriate with ectopic, or presumed ectopic, pregnancy management. Appropriate monitoring did not occur in this case. Each of these errors (following up on serum hCG levels and the inadequacy of notations about the possibility of ectopic pregnancy) seem inconsistent with the usual standard of care. Furthermore, as a result of the outcome, the only future option for the patient to pursue pregnancy was IVF.

Other legal issues

There are a number of other legal issues that are associated with the topic of ectopic pregnancy. There is evidence, for example, that Catholic and non-Catholic hospitals treat ectopic pregnancies differently,²³ which may reflect different views on taking a life or the use of methotrexate and its association with abortion.²⁴ In addition, the possibility of an increase in future ectopic pregnancies is one of the “risks” of abortion that pro-life organizations have pushed to see included in abortion informed consent.²⁵ This has led some commentators to conclude that some Catholic hospitals violate federal law in managing ectopic pregnancy. There is also evidence of “overwhelming rates of medical misinformation on pregnancy center websites, including a link between abortion and ectopic pregnancy.”²⁶

The fact that cesarean deliveries are related to an increased risk for ectopic pregnancy (because of the risk of cesarean scar ectopic pregnancy) also has been cited as information that should play a role in the consent process for cesarean delivery.²⁷ In terms of liability, failed tubal ligation leads to a 33% risk of ectopic pregnancy.²⁸ The risk of ectopic pregnancy is also commonly included in surrogacy contracts.²⁹

Why the outcome was for the defense

The opening hypothetical case illustrates some of the uncertainties of medical malpractice cases. As noted, there appeared a deviation from the usual standard of care, particularly the failure to follow up on the serum hCG level. The weakness in the medical record, failing to note the possibility of ectopic pregnancy, also was probably an error but, apparently, the court felt that this did not result in any harm to the patient.

The question arises of how there would be a defense verdict in light of the failure to track consecutive serum hCG levels. A speculative explanation is that there are many uncertainties in most lawsuits. Procedural problems may result in a case being limited, expert witnesses are essential to both the plaintiff and defense, with the quality of their review and testimony possibly uneven. Judges and juries may rely on one expert witness rather than another, juries vary, and the quality of advocacy differs. Any of these situations can contribute to the unpredictability of the outcome of a case. In the case above, the liability was somewhat uncertain, and the various other factors tipped in favor of a defense verdict. ●

While 2020 was a challenge to say the least, obstetrician-gynecologists remained on the frontline caring for women through it all. Life continued despite the COVID-19 pandemic: prenatal care was delivered, albeit at times in different ways; babies were born; and our role in improving outcomes for women and their children became even more important. This year’s Update focuses on clinical guidelines centered on safety and optimal outcomes for women and children.

ACOG and SMFM update guidance on FGR management

American College of Obstetricians and Gynecologists. Practice advisory: Updated guidance regarding fetal growth restriction. September 2020. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/09/updated-guidance-regarding-fetal-growth-restriction. Accessed December 18, 2020.

Fetal growth restriction (FGR) affects up to 10% of pregnancies and is a leading cause of infant morbidity and mortality. Suboptimal fetal growth can have lasting negative effects on development into early childhood and, some hypothesize, even into adulthood.^1,2 Antenatal detection of fetuses with FGR is critical so that antenatal testing can be implemented in an attempt to deliver improved clinical outcomes. FGR is defined by several different diagnostic criteria, and many studies have been conducted to determine how best to diagnose this condition.

In September 2020, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory regarding guidance on FGR in an effort to align the ACOG Practice Bulletin No. 204, ACOG Committee Opinion No. 764, and SMFM (Society for Maternal-Fetal Medicine) Consult Series No. 52.^3-5 This guidance updates and replaces prior guidelines, with an emphasis on 3 notable changes.

FGR definition, workup have changed

While the original definition of FGR was an estimated fetal weight (EFW) of less than the 10th percentile for gestational age, a similar level of accuracy in prediction of subsequent small for gestational age (SGA) at birth has been shown when this or an abdominal circumference (AC) of less than the 10th percentile is used. Based on these findings, SMFM now recommends that FGR be defined as an EFW or AC of less than the 10th percentile for gestational age.

Recent studies have done head-to-head comparisons of different methods of estimating fetal weight to determine the best detection and pregnancy outcome improvement in FGR. In all instances, the Hadlock formula has continued to more accurately estimate fetal weight, prediction of SGA, and composite neonatal morbidity. As such, new guidelines recommend that population-based fetal growth references (that is, the Hadlock formula) should be used to determine ultrasonography-derived fetal weight percentiles.

The new guidance also suggests classification of FGR based on gestational age at onset, with early FGR at less than 32 weeks and late FGR at 32 or more weeks. The definition of severe FGR is reserved for fetuses with an EFW of less than the 3rd percentile. A diagnosis of FGR should prompt the recommendation for a detailed obstetric ultrasonography. Diagnostic genetic testing should be offered in cases of early-onset FGR, concomitant sonographic abnormalities, and/or polyhydramnios. Routine serum screening for toxoplasmosis, rubella, herpes, or cytomegalovirus (CMV) should not be done unless there are risk factors for infection. If amniocentesis is performed for genetic diagnostic testing, consideration can be made for polymerase chain reaction for CMV in the amniotic fluid.

Continue to: Timing of delivery in isolated FGR...

Timing of delivery in isolated FGR

A complicating factor in diagnosing FGR is distinguishing between the pathologically growth-restricted fetus and the constitutionally small fetus. Antenatal testing and serial umbilical artery Doppler assessment should be done following diagnosis of FGR to monitor for evidence of fetal compromise until delivery is planned.

The current ACOG Practice Bulletin No. 204 and Committee Opinion No. 764 recommend delivery between 38 0/7 and 39 6/7 weeks in the setting of isolated FGR with reassuring fetal testing and umbilical artery Doppler assessment.To further refine this, the new recommendations use the growth percentiles. In cases of isolated FGR with EFW between the 3rd and 10th percentile in the setting of normal umbilical artery Doppler, delivery is recommended between 38 and 39 weeks’ gestation. In cases of isolated FGR with EFW of less than the 3rd percentile (severe FGR) in the setting of normal umbilical artery Doppler, delivery is recommended at 37 weeks.

Timing of delivery in complicated FGR

A normal umbilical artery Doppler reflects the low impedance that is necessary for continuous forward flow of blood to the fetus. Abnormal umbilical artery Doppler signifies aberrations of this low-pressure system that affect the amount of continuous forward flow during diastole of the cardiac cycle. With continued compromise, there is progression to absent end-diastolic velocity (AEDV) and, most concerning, reversed end-diastolic velocity (REDV).

Serial umbilical artery Doppler assessment should be done following diagnosis of FGR to monitor for progression that is associated with perinatal mortality, since intervention can be initiated in the form of delivery. Delivery at 37 weeks is recommended for FGR with elevated umbilical artery Doppler of greater than the 95th percentile for gestational age. For FGR with AEDV, delivery is recommended between 33 and 34 weeks of gestation and for FGR with REDV between 30 and 32 weeks, as the neonatal morbidity and mortality associated with continuing the pregnancy outweighs the risks of prematurity in this setting. Because of the abnormal placental-fetal circulation in FGR complicated by AEDV/REDV, there may be a higher likelihood of fetal intolerance of labor and cesarean delivery (CD) may be considered.

Continue to: New recommendations for PROM management...

New recommendations for PROM management

American College of Obstetricians and Gynecologists Committee on Practice Bulletins–Obstetrics. ACOG practice bulletin no. 217: Prelabor rupture of membranes. Obstet Gynecol. 2020;135:e80-e97.

Rupture of membranes prior to the onset of labor occurs at term in 8% of pregnancies and in the preterm period in 2% to 3% of pregnancies.⁶ Accurate diagnosis, gestational age, evidence of infection, and discussion of the risks and benefits to the mother and fetus/neonate are necessary to optimize outcomes. In the absence of other indications for delivery, a gestational age of 34 or more weeks traditionally has been the cutoff to proceed with delivery, although this has not been globally agreed on and/or practiced.

ACOG has published a comprehensive update that incorporates the results of the PPROMT trial and other recommendations for the diagnosis and management of both term and preterm prelabor rupture of membranes (PROM).^6,7

Making the diagnosis

Diagnosis of PROM usually can be made clinically via history and the classic triad of physical exam findings—pooling of fluid, basic pH, and ferning; some institutions also use commercially available tests that detect placental-derived proteins. Both ACOG and the US Food and Drug Administration caution against using these tests alone without clinical evaluation due to concern for false-positives and false-negatives that lead to adverse maternal and fetal/neonatal outcomes. For equivocal cases, ultrasonography for amniotic fluid evaluation and ultrasonography-guided dye tests can be used to assist in accurate diagnosis, especially in the preterm period in which there are significant implications for pregnancy management.

PROM management depends on gestational age

All management recommendations require reassuring fetal testing, evaluation for infection, and no other contraindications to expectant management. Once these are established, the most important determinant of PROM management then becomes gestational age.

Previable PROM

Previable PROM (usually defined as less than 23–24 weeks) has high risks of both maternal and fetal/neonatal morbidity and mortality from infection, hemorrhage, pulmonary hypoplasia, and extreme prematurity. These very difficult cases benefit from a multidisciplinary approach to patient counseling regarding expectant management versus immediate delivery.

If expectant management is chosen, outpatient management with close monitoring for signs of maternal infection may be done until an agreed on gestational age of viability. Then inpatient management with fetal monitoring, corticosteroids, tocolysis, magnesium for neuroprotection, and group B streptococcus (GBS) prophylaxis may be considered as appropriate.

Preterm PROM at less than 34 weeks

If the mother and fetus are otherwise stable, PROM at less than 34 weeks warrants inpatient expectant management with close maternal and fetal monitoring for signs of infection and labor. Management includes latency antibiotics, antenatal corticosteroids, magnesium for neuroprotection if less than 32 weeks’ gestation and at risk for imminent delivery, and GBS prophylaxis. While tocolysis may increase latency and help with steroid course completion, it should be used cautiously and avoided in cases of abruption or chorioamnionitis. Although there is no definitive recommendation published, a rescue course of steroids may be considered as appropriate but should not delay an indicated delivery.

Continue to: Late preterm PROM...

Late preterm PROM

The biggest change to clinical management in this ACOG Practice Bulletin is for late preterm (34–36 6/7 weeks) PROM, with the recommendation for either immediate delivery or expectant management up to 37 weeks stemming from the PPROMPT study by Morris and colleagues.⁷

From the neonatal perspective, no difference has been demonstrated between immediate delivery and expectant management for neonatal sepsis or a composite neonatal morbidity and mortality. Expectant management may be preferred from the neonatal point of view as immediate delivery was associated with an increased rate of neonatal respiratory distress, mechanical ventilation, and length of stay in the neonatal intensive care unit. The potential for long-term neurodevelopmental outcomes of delivery at 34 versus 37 weeks also should be considered.

From the maternal perspective, expectant management has an increased risk of antepartum and postpartum hemorrhage, fever, antibiotic use, and maternal length of stay, but a decreased risk of CD.

A late preterm steroid course can be considered if delivery is planned in no less than 24 hours and likely to occur in the next 7 days and if the patient has not already received a course of steroids. A rescue course of steroids is not indicated if the patient received a steroid course prior in the pregnancy. While appropriate GBS prophylaxis is recommended, latency antibiotics and tocolysis are not, and delivery should not be delayed if chorioamnionitis is diagnosed.

Ultimately, preterm PROM management with a stable mother and fetus at or beyond 34 weeks requires comprehensive counseling of the risks and benefits for both mother and fetus/neonate. A multidisciplinary team that together counsels the patient also may help with this shared decision making.

Term PROM

For patients with term PROM, delivery is recommended. Although a short period of expectant management for 12 to 24 hours is reported as “reasonable,” the risk of infection increases with the length of rupture of membranes. Therefore, induction of labor or CD soon after rupture of membranes is recommended for patients who are GBS positive and is preferred for all others.

VTE prophylaxis in pregnancy: Regimen adjustments, CD strategies, and COVID-19 considerations

Birsner ML, Turrentine M, Pettker CM, et al. ACOG practice advisory: Options for peripartum anticoagulation in areas affected by shortage of unfractionated heparin. March 2020. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/03/options-for-peripartum-anticoagulation-in-areas-affected-by-shortage-of-unfractionated-heparin. Accessed December 8, 2020.

Pacheco LD, Saade G, Metz TD. Society for Maternal-Fetal Medicine Consult Series No. 51: Thromboembolism prophylaxis for cesarean delivery. Am J Obstet Gynecol. 2020;223:B11-B17

Venous thromboembolism (VTE) prophylaxis is a timely topic for a number of reasons. First, a shortage of unfractionated heparin prompted an ACOG Practice Advisory, endorsed by SMFM and the Society for Obstetric Anesthesia and Perinatology, regarding use of low molecular weight heparin (LMWH) in the peripartum period.⁸ In addition, SMFM released updated recommendations for VTE prophylaxis for CD as part of the SMFM Consult Series.⁹ Finally, there is evidence that COVID-19 infection may increase the risk of coagulopathy, leading to consideration of additional VTE prophylaxis for pregnant and postpartum women with COVID-19.

Candidates for prophylaxis

As recommended by the ACOG Practice Bulletin on thromboembolism in pregnancy, women who may require VTE prophylaxis during pregnancy and/or the postpartum period include those with¹⁰:

• VTE diagnosed during pregnancy
• a history of VTE, including during pregnancy or with use of hormonal contraception
• a history of thrombophilia with or without a personal or family history of VTE.

For these patients, LMWH has many advantages over unfractionated heparin, including ease of use and reliability of dosing. It generally is preferred in pregnancy and postpartum (for both prophylactic and therapeutic anticoagulation) by patients and providers.

The Practice Bulletin references a strategy that describes converting LMWH to unfractionated heparin at around 36 weeks’ gestation in preparation for delivery because unfractionated heparin has the advantage of a shorter half-life and the option for anticoagulation reversal with protamine sulfate. In the Practice Advisory, a global shortage of unfractionated heparin and an argument that the above conversion was less about concern for maternal hemorrhage and more about avoiding spinal and epidural hematomas led to the following recommendations for continued use of LMWH through delivery:

• LMWH heparin can be discontinued in a planned fashion prior to scheduled induction of labor or CD (generally 12 hours for prophylactic dosing and 24 hours for intermediate dosing).
• Patients in spontaneous labor may receive neuraxial anesthesia 12 hours after the last prophylactic dose and 24 hours after the last intermediate dose of LMWH.
• Patients who require anticoagulation during pregnancy should be counseled that if they have vaginal bleeding, leakage of fluid, or regular contractions they should be evaluated prior to taking their next dose of anticoagulant.
• In the absence of other complications, delivery should not be before 39 weeks for the indication of anticoagulation requirement alone.

Continue to: Managing VTE risk in CD...

Managing VTE risk in CD

Recognizing that VTE is a major cause of maternal morbidity and mortality, as well as the variety of the published guidelines for VTE prophylaxis after CD, the SMFM Consult Series provides recommendations to assist clinicians caring for postpartum women after CD. As reviewed in the ACOG Practice Bulletin, there are good data to support pharmacologic prophylaxis during pregnancy and the postpartum period for women with a history of VTE or a thrombophilia. Solid evidence is lacking, however, for what to do for women who have a CD without this history but may have other potential risk factors for VTE, such as obesity, preeclampsia, and transfusion requirement. Universal pharmacologic prophylaxis also is not yet supported by evidence. SMFM supports LMWH as the preferred medication in pregnancy and postpartum and provides these additional recommendations:

• All women who have a CD should have sequential compression devices (SCDs) placed prior to surgery and continued until they are ambulatory.
• Women with a history of VTE or thrombophilia without history of VTE should have SCDs and pharmacologic VTE prophylaxis for 6 weeks postpartum.
• Intermediate dosing of LMWH is recommended for patients with class III obesity.
• Institutions should develop patient safety bundles for VTE prophylaxis to identify additional risk factors that may warrant pharmacologic prophylaxis after CD in select patients.

Our approach to patients with COVID-19 infection

At our institution, we recently incorporated a VTE prophylaxis protocol into our electronic medical record that provides risk stratification for each patient. In addition to the above recommendations, our patients may qualify for short-term in-house or longer postpartum prophylaxis depending on risk factors.

A new risk factor in recent months is COVID-19 infection, which appears to increase the risk of coagulopathy, especially in patients with disease severe enough to warrant hospitalization. Given the potential for additive risk in pregnancy, in consult with our medicine colleagues, we have placed some of our more ill hospitalized pregnant patients on a course of prophylactic LMWH both in the hospital and after discharge independent of delivery status or mode of delivery. ●

While 2020 was a challenge to say the least, obstetrician-gynecologists remained on the frontline caring for women through it all. Life continued despite the COVID-19 pandemic: prenatal care was delivered, albeit at times in different ways; babies were born; and our role in improving outcomes for women and their children became even more important. This year’s Update focuses on clinical guidelines centered on safety and optimal outcomes for women and children.

ACOG and SMFM update guidance on FGR management

American College of Obstetricians and Gynecologists. Practice advisory: Updated guidance regarding fetal growth restriction. September 2020. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/09/updated-guidance-regarding-fetal-growth-restriction. Accessed December 18, 2020.

Fetal growth restriction (FGR) affects up to 10% of pregnancies and is a leading cause of infant morbidity and mortality. Suboptimal fetal growth can have lasting negative effects on development into early childhood and, some hypothesize, even into adulthood.^1,2 Antenatal detection of fetuses with FGR is critical so that antenatal testing can be implemented in an attempt to deliver improved clinical outcomes. FGR is defined by several different diagnostic criteria, and many studies have been conducted to determine how best to diagnose this condition.

In September 2020, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory regarding guidance on FGR in an effort to align the ACOG Practice Bulletin No. 204, ACOG Committee Opinion No. 764, and SMFM (Society for Maternal-Fetal Medicine) Consult Series No. 52.^3-5 This guidance updates and replaces prior guidelines, with an emphasis on 3 notable changes.

FGR definition, workup have changed

While the original definition of FGR was an estimated fetal weight (EFW) of less than the 10th percentile for gestational age, a similar level of accuracy in prediction of subsequent small for gestational age (SGA) at birth has been shown when this or an abdominal circumference (AC) of less than the 10th percentile is used. Based on these findings, SMFM now recommends that FGR be defined as an EFW or AC of less than the 10th percentile for gestational age.

Recent studies have done head-to-head comparisons of different methods of estimating fetal weight to determine the best detection and pregnancy outcome improvement in FGR. In all instances, the Hadlock formula has continued to more accurately estimate fetal weight, prediction of SGA, and composite neonatal morbidity. As such, new guidelines recommend that population-based fetal growth references (that is, the Hadlock formula) should be used to determine ultrasonography-derived fetal weight percentiles.

The new guidance also suggests classification of FGR based on gestational age at onset, with early FGR at less than 32 weeks and late FGR at 32 or more weeks. The definition of severe FGR is reserved for fetuses with an EFW of less than the 3rd percentile. A diagnosis of FGR should prompt the recommendation for a detailed obstetric ultrasonography. Diagnostic genetic testing should be offered in cases of early-onset FGR, concomitant sonographic abnormalities, and/or polyhydramnios. Routine serum screening for toxoplasmosis, rubella, herpes, or cytomegalovirus (CMV) should not be done unless there are risk factors for infection. If amniocentesis is performed for genetic diagnostic testing, consideration can be made for polymerase chain reaction for CMV in the amniotic fluid.

Continue to: Timing of delivery in isolated FGR...

Timing of delivery in isolated FGR

A complicating factor in diagnosing FGR is distinguishing between the pathologically growth-restricted fetus and the constitutionally small fetus. Antenatal testing and serial umbilical artery Doppler assessment should be done following diagnosis of FGR to monitor for evidence of fetal compromise until delivery is planned.

The current ACOG Practice Bulletin No. 204 and Committee Opinion No. 764 recommend delivery between 38 0/7 and 39 6/7 weeks in the setting of isolated FGR with reassuring fetal testing and umbilical artery Doppler assessment.To further refine this, the new recommendations use the growth percentiles. In cases of isolated FGR with EFW between the 3rd and 10th percentile in the setting of normal umbilical artery Doppler, delivery is recommended between 38 and 39 weeks’ gestation. In cases of isolated FGR with EFW of less than the 3rd percentile (severe FGR) in the setting of normal umbilical artery Doppler, delivery is recommended at 37 weeks.

Timing of delivery in complicated FGR

A normal umbilical artery Doppler reflects the low impedance that is necessary for continuous forward flow of blood to the fetus. Abnormal umbilical artery Doppler signifies aberrations of this low-pressure system that affect the amount of continuous forward flow during diastole of the cardiac cycle. With continued compromise, there is progression to absent end-diastolic velocity (AEDV) and, most concerning, reversed end-diastolic velocity (REDV).

Serial umbilical artery Doppler assessment should be done following diagnosis of FGR to monitor for progression that is associated with perinatal mortality, since intervention can be initiated in the form of delivery. Delivery at 37 weeks is recommended for FGR with elevated umbilical artery Doppler of greater than the 95th percentile for gestational age. For FGR with AEDV, delivery is recommended between 33 and 34 weeks of gestation and for FGR with REDV between 30 and 32 weeks, as the neonatal morbidity and mortality associated with continuing the pregnancy outweighs the risks of prematurity in this setting. Because of the abnormal placental-fetal circulation in FGR complicated by AEDV/REDV, there may be a higher likelihood of fetal intolerance of labor and cesarean delivery (CD) may be considered.

Continue to: New recommendations for PROM management...

New recommendations for PROM management

American College of Obstetricians and Gynecologists Committee on Practice Bulletins–Obstetrics. ACOG practice bulletin no. 217: Prelabor rupture of membranes. Obstet Gynecol. 2020;135:e80-e97.

Rupture of membranes prior to the onset of labor occurs at term in 8% of pregnancies and in the preterm period in 2% to 3% of pregnancies.⁶ Accurate diagnosis, gestational age, evidence of infection, and discussion of the risks and benefits to the mother and fetus/neonate are necessary to optimize outcomes. In the absence of other indications for delivery, a gestational age of 34 or more weeks traditionally has been the cutoff to proceed with delivery, although this has not been globally agreed on and/or practiced.

ACOG has published a comprehensive update that incorporates the results of the PPROMT trial and other recommendations for the diagnosis and management of both term and preterm prelabor rupture of membranes (PROM).^6,7

Making the diagnosis

Diagnosis of PROM usually can be made clinically via history and the classic triad of physical exam findings—pooling of fluid, basic pH, and ferning; some institutions also use commercially available tests that detect placental-derived proteins. Both ACOG and the US Food and Drug Administration caution against using these tests alone without clinical evaluation due to concern for false-positives and false-negatives that lead to adverse maternal and fetal/neonatal outcomes. For equivocal cases, ultrasonography for amniotic fluid evaluation and ultrasonography-guided dye tests can be used to assist in accurate diagnosis, especially in the preterm period in which there are significant implications for pregnancy management.

PROM management depends on gestational age

All management recommendations require reassuring fetal testing, evaluation for infection, and no other contraindications to expectant management. Once these are established, the most important determinant of PROM management then becomes gestational age.

Previable PROM

Previable PROM (usually defined as less than 23–24 weeks) has high risks of both maternal and fetal/neonatal morbidity and mortality from infection, hemorrhage, pulmonary hypoplasia, and extreme prematurity. These very difficult cases benefit from a multidisciplinary approach to patient counseling regarding expectant management versus immediate delivery.

If expectant management is chosen, outpatient management with close monitoring for signs of maternal infection may be done until an agreed on gestational age of viability. Then inpatient management with fetal monitoring, corticosteroids, tocolysis, magnesium for neuroprotection, and group B streptococcus (GBS) prophylaxis may be considered as appropriate.

Preterm PROM at less than 34 weeks

If the mother and fetus are otherwise stable, PROM at less than 34 weeks warrants inpatient expectant management with close maternal and fetal monitoring for signs of infection and labor. Management includes latency antibiotics, antenatal corticosteroids, magnesium for neuroprotection if less than 32 weeks’ gestation and at risk for imminent delivery, and GBS prophylaxis. While tocolysis may increase latency and help with steroid course completion, it should be used cautiously and avoided in cases of abruption or chorioamnionitis. Although there is no definitive recommendation published, a rescue course of steroids may be considered as appropriate but should not delay an indicated delivery.

Continue to: Late preterm PROM...

Late preterm PROM

The biggest change to clinical management in this ACOG Practice Bulletin is for late preterm (34–36 6/7 weeks) PROM, with the recommendation for either immediate delivery or expectant management up to 37 weeks stemming from the PPROMPT study by Morris and colleagues.⁷

From the neonatal perspective, no difference has been demonstrated between immediate delivery and expectant management for neonatal sepsis or a composite neonatal morbidity and mortality. Expectant management may be preferred from the neonatal point of view as immediate delivery was associated with an increased rate of neonatal respiratory distress, mechanical ventilation, and length of stay in the neonatal intensive care unit. The potential for long-term neurodevelopmental outcomes of delivery at 34 versus 37 weeks also should be considered.

From the maternal perspective, expectant management has an increased risk of antepartum and postpartum hemorrhage, fever, antibiotic use, and maternal length of stay, but a decreased risk of CD.

A late preterm steroid course can be considered if delivery is planned in no less than 24 hours and likely to occur in the next 7 days and if the patient has not already received a course of steroids. A rescue course of steroids is not indicated if the patient received a steroid course prior in the pregnancy. While appropriate GBS prophylaxis is recommended, latency antibiotics and tocolysis are not, and delivery should not be delayed if chorioamnionitis is diagnosed.

Ultimately, preterm PROM management with a stable mother and fetus at or beyond 34 weeks requires comprehensive counseling of the risks and benefits for both mother and fetus/neonate. A multidisciplinary team that together counsels the patient also may help with this shared decision making.

Term PROM

For patients with term PROM, delivery is recommended. Although a short period of expectant management for 12 to 24 hours is reported as “reasonable,” the risk of infection increases with the length of rupture of membranes. Therefore, induction of labor or CD soon after rupture of membranes is recommended for patients who are GBS positive and is preferred for all others.

VTE prophylaxis in pregnancy: Regimen adjustments, CD strategies, and COVID-19 considerations

Birsner ML, Turrentine M, Pettker CM, et al. ACOG practice advisory: Options for peripartum anticoagulation in areas affected by shortage of unfractionated heparin. March 2020. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/03/options-for-peripartum-anticoagulation-in-areas-affected-by-shortage-of-unfractionated-heparin. Accessed December 8, 2020.

Pacheco LD, Saade G, Metz TD. Society for Maternal-Fetal Medicine Consult Series No. 51: Thromboembolism prophylaxis for cesarean delivery. Am J Obstet Gynecol. 2020;223:B11-B17

Venous thromboembolism (VTE) prophylaxis is a timely topic for a number of reasons. First, a shortage of unfractionated heparin prompted an ACOG Practice Advisory, endorsed by SMFM and the Society for Obstetric Anesthesia and Perinatology, regarding use of low molecular weight heparin (LMWH) in the peripartum period.⁸ In addition, SMFM released updated recommendations for VTE prophylaxis for CD as part of the SMFM Consult Series.⁹ Finally, there is evidence that COVID-19 infection may increase the risk of coagulopathy, leading to consideration of additional VTE prophylaxis for pregnant and postpartum women with COVID-19.

Candidates for prophylaxis

As recommended by the ACOG Practice Bulletin on thromboembolism in pregnancy, women who may require VTE prophylaxis during pregnancy and/or the postpartum period include those with¹⁰:

• VTE diagnosed during pregnancy
• a history of VTE, including during pregnancy or with use of hormonal contraception
• a history of thrombophilia with or without a personal or family history of VTE.

For these patients, LMWH has many advantages over unfractionated heparin, including ease of use and reliability of dosing. It generally is preferred in pregnancy and postpartum (for both prophylactic and therapeutic anticoagulation) by patients and providers.

The Practice Bulletin references a strategy that describes converting LMWH to unfractionated heparin at around 36 weeks’ gestation in preparation for delivery because unfractionated heparin has the advantage of a shorter half-life and the option for anticoagulation reversal with protamine sulfate. In the Practice Advisory, a global shortage of unfractionated heparin and an argument that the above conversion was less about concern for maternal hemorrhage and more about avoiding spinal and epidural hematomas led to the following recommendations for continued use of LMWH through delivery:

• LMWH heparin can be discontinued in a planned fashion prior to scheduled induction of labor or CD (generally 12 hours for prophylactic dosing and 24 hours for intermediate dosing).
• Patients in spontaneous labor may receive neuraxial anesthesia 12 hours after the last prophylactic dose and 24 hours after the last intermediate dose of LMWH.
• Patients who require anticoagulation during pregnancy should be counseled that if they have vaginal bleeding, leakage of fluid, or regular contractions they should be evaluated prior to taking their next dose of anticoagulant.
• In the absence of other complications, delivery should not be before 39 weeks for the indication of anticoagulation requirement alone.

Continue to: Managing VTE risk in CD...

Managing VTE risk in CD

Recognizing that VTE is a major cause of maternal morbidity and mortality, as well as the variety of the published guidelines for VTE prophylaxis after CD, the SMFM Consult Series provides recommendations to assist clinicians caring for postpartum women after CD. As reviewed in the ACOG Practice Bulletin, there are good data to support pharmacologic prophylaxis during pregnancy and the postpartum period for women with a history of VTE or a thrombophilia. Solid evidence is lacking, however, for what to do for women who have a CD without this history but may have other potential risk factors for VTE, such as obesity, preeclampsia, and transfusion requirement. Universal pharmacologic prophylaxis also is not yet supported by evidence. SMFM supports LMWH as the preferred medication in pregnancy and postpartum and provides these additional recommendations:

• All women who have a CD should have sequential compression devices (SCDs) placed prior to surgery and continued until they are ambulatory.
• Women with a history of VTE or thrombophilia without history of VTE should have SCDs and pharmacologic VTE prophylaxis for 6 weeks postpartum.
• Intermediate dosing of LMWH is recommended for patients with class III obesity.
• Institutions should develop patient safety bundles for VTE prophylaxis to identify additional risk factors that may warrant pharmacologic prophylaxis after CD in select patients.

Our approach to patients with COVID-19 infection

At our institution, we recently incorporated a VTE prophylaxis protocol into our electronic medical record that provides risk stratification for each patient. In addition to the above recommendations, our patients may qualify for short-term in-house or longer postpartum prophylaxis depending on risk factors.

A new risk factor in recent months is COVID-19 infection, which appears to increase the risk of coagulopathy, especially in patients with disease severe enough to warrant hospitalization. Given the potential for additive risk in pregnancy, in consult with our medicine colleagues, we have placed some of our more ill hospitalized pregnant patients on a course of prophylactic LMWH both in the hospital and after discharge independent of delivery status or mode of delivery. ●

While 2020 was a challenge to say the least, obstetrician-gynecologists remained on the frontline caring for women through it all. Life continued despite the COVID-19 pandemic: prenatal care was delivered, albeit at times in different ways; babies were born; and our role in improving outcomes for women and their children became even more important. This year’s Update focuses on clinical guidelines centered on safety and optimal outcomes for women and children.

ACOG and SMFM update guidance on FGR management

American College of Obstetricians and Gynecologists. Practice advisory: Updated guidance regarding fetal growth restriction. September 2020. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/09/updated-guidance-regarding-fetal-growth-restriction. Accessed December 18, 2020.

Fetal growth restriction (FGR) affects up to 10% of pregnancies and is a leading cause of infant morbidity and mortality. Suboptimal fetal growth can have lasting negative effects on development into early childhood and, some hypothesize, even into adulthood.^1,2 Antenatal detection of fetuses with FGR is critical so that antenatal testing can be implemented in an attempt to deliver improved clinical outcomes. FGR is defined by several different diagnostic criteria, and many studies have been conducted to determine how best to diagnose this condition.

In September 2020, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory regarding guidance on FGR in an effort to align the ACOG Practice Bulletin No. 204, ACOG Committee Opinion No. 764, and SMFM (Society for Maternal-Fetal Medicine) Consult Series No. 52.^3-5 This guidance updates and replaces prior guidelines, with an emphasis on 3 notable changes.

FGR definition, workup have changed

While the original definition of FGR was an estimated fetal weight (EFW) of less than the 10th percentile for gestational age, a similar level of accuracy in prediction of subsequent small for gestational age (SGA) at birth has been shown when this or an abdominal circumference (AC) of less than the 10th percentile is used. Based on these findings, SMFM now recommends that FGR be defined as an EFW or AC of less than the 10th percentile for gestational age.

Recent studies have done head-to-head comparisons of different methods of estimating fetal weight to determine the best detection and pregnancy outcome improvement in FGR. In all instances, the Hadlock formula has continued to more accurately estimate fetal weight, prediction of SGA, and composite neonatal morbidity. As such, new guidelines recommend that population-based fetal growth references (that is, the Hadlock formula) should be used to determine ultrasonography-derived fetal weight percentiles.

The new guidance also suggests classification of FGR based on gestational age at onset, with early FGR at less than 32 weeks and late FGR at 32 or more weeks. The definition of severe FGR is reserved for fetuses with an EFW of less than the 3rd percentile. A diagnosis of FGR should prompt the recommendation for a detailed obstetric ultrasonography. Diagnostic genetic testing should be offered in cases of early-onset FGR, concomitant sonographic abnormalities, and/or polyhydramnios. Routine serum screening for toxoplasmosis, rubella, herpes, or cytomegalovirus (CMV) should not be done unless there are risk factors for infection. If amniocentesis is performed for genetic diagnostic testing, consideration can be made for polymerase chain reaction for CMV in the amniotic fluid.

Continue to: Timing of delivery in isolated FGR...

Timing of delivery in isolated FGR

A complicating factor in diagnosing FGR is distinguishing between the pathologically growth-restricted fetus and the constitutionally small fetus. Antenatal testing and serial umbilical artery Doppler assessment should be done following diagnosis of FGR to monitor for evidence of fetal compromise until delivery is planned.

The current ACOG Practice Bulletin No. 204 and Committee Opinion No. 764 recommend delivery between 38 0/7 and 39 6/7 weeks in the setting of isolated FGR with reassuring fetal testing and umbilical artery Doppler assessment.To further refine this, the new recommendations use the growth percentiles. In cases of isolated FGR with EFW between the 3rd and 10th percentile in the setting of normal umbilical artery Doppler, delivery is recommended between 38 and 39 weeks’ gestation. In cases of isolated FGR with EFW of less than the 3rd percentile (severe FGR) in the setting of normal umbilical artery Doppler, delivery is recommended at 37 weeks.

Timing of delivery in complicated FGR

A normal umbilical artery Doppler reflects the low impedance that is necessary for continuous forward flow of blood to the fetus. Abnormal umbilical artery Doppler signifies aberrations of this low-pressure system that affect the amount of continuous forward flow during diastole of the cardiac cycle. With continued compromise, there is progression to absent end-diastolic velocity (AEDV) and, most concerning, reversed end-diastolic velocity (REDV).

Serial umbilical artery Doppler assessment should be done following diagnosis of FGR to monitor for progression that is associated with perinatal mortality, since intervention can be initiated in the form of delivery. Delivery at 37 weeks is recommended for FGR with elevated umbilical artery Doppler of greater than the 95th percentile for gestational age. For FGR with AEDV, delivery is recommended between 33 and 34 weeks of gestation and for FGR with REDV between 30 and 32 weeks, as the neonatal morbidity and mortality associated with continuing the pregnancy outweighs the risks of prematurity in this setting. Because of the abnormal placental-fetal circulation in FGR complicated by AEDV/REDV, there may be a higher likelihood of fetal intolerance of labor and cesarean delivery (CD) may be considered.

Continue to: New recommendations for PROM management...

New recommendations for PROM management

American College of Obstetricians and Gynecologists Committee on Practice Bulletins–Obstetrics. ACOG practice bulletin no. 217: Prelabor rupture of membranes. Obstet Gynecol. 2020;135:e80-e97.

Rupture of membranes prior to the onset of labor occurs at term in 8% of pregnancies and in the preterm period in 2% to 3% of pregnancies.⁶ Accurate diagnosis, gestational age, evidence of infection, and discussion of the risks and benefits to the mother and fetus/neonate are necessary to optimize outcomes. In the absence of other indications for delivery, a gestational age of 34 or more weeks traditionally has been the cutoff to proceed with delivery, although this has not been globally agreed on and/or practiced.

ACOG has published a comprehensive update that incorporates the results of the PPROMT trial and other recommendations for the diagnosis and management of both term and preterm prelabor rupture of membranes (PROM).^6,7

Making the diagnosis

Diagnosis of PROM usually can be made clinically via history and the classic triad of physical exam findings—pooling of fluid, basic pH, and ferning; some institutions also use commercially available tests that detect placental-derived proteins. Both ACOG and the US Food and Drug Administration caution against using these tests alone without clinical evaluation due to concern for false-positives and false-negatives that lead to adverse maternal and fetal/neonatal outcomes. For equivocal cases, ultrasonography for amniotic fluid evaluation and ultrasonography-guided dye tests can be used to assist in accurate diagnosis, especially in the preterm period in which there are significant implications for pregnancy management.

PROM management depends on gestational age

All management recommendations require reassuring fetal testing, evaluation for infection, and no other contraindications to expectant management. Once these are established, the most important determinant of PROM management then becomes gestational age.

Previable PROM

Previable PROM (usually defined as less than 23–24 weeks) has high risks of both maternal and fetal/neonatal morbidity and mortality from infection, hemorrhage, pulmonary hypoplasia, and extreme prematurity. These very difficult cases benefit from a multidisciplinary approach to patient counseling regarding expectant management versus immediate delivery.

If expectant management is chosen, outpatient management with close monitoring for signs of maternal infection may be done until an agreed on gestational age of viability. Then inpatient management with fetal monitoring, corticosteroids, tocolysis, magnesium for neuroprotection, and group B streptococcus (GBS) prophylaxis may be considered as appropriate.

Preterm PROM at less than 34 weeks

If the mother and fetus are otherwise stable, PROM at less than 34 weeks warrants inpatient expectant management with close maternal and fetal monitoring for signs of infection and labor. Management includes latency antibiotics, antenatal corticosteroids, magnesium for neuroprotection if less than 32 weeks’ gestation and at risk for imminent delivery, and GBS prophylaxis. While tocolysis may increase latency and help with steroid course completion, it should be used cautiously and avoided in cases of abruption or chorioamnionitis. Although there is no definitive recommendation published, a rescue course of steroids may be considered as appropriate but should not delay an indicated delivery.

Continue to: Late preterm PROM...

Late preterm PROM

The biggest change to clinical management in this ACOG Practice Bulletin is for late preterm (34–36 6/7 weeks) PROM, with the recommendation for either immediate delivery or expectant management up to 37 weeks stemming from the PPROMPT study by Morris and colleagues.⁷

From the neonatal perspective, no difference has been demonstrated between immediate delivery and expectant management for neonatal sepsis or a composite neonatal morbidity and mortality. Expectant management may be preferred from the neonatal point of view as immediate delivery was associated with an increased rate of neonatal respiratory distress, mechanical ventilation, and length of stay in the neonatal intensive care unit. The potential for long-term neurodevelopmental outcomes of delivery at 34 versus 37 weeks also should be considered.

From the maternal perspective, expectant management has an increased risk of antepartum and postpartum hemorrhage, fever, antibiotic use, and maternal length of stay, but a decreased risk of CD.

A late preterm steroid course can be considered if delivery is planned in no less than 24 hours and likely to occur in the next 7 days and if the patient has not already received a course of steroids. A rescue course of steroids is not indicated if the patient received a steroid course prior in the pregnancy. While appropriate GBS prophylaxis is recommended, latency antibiotics and tocolysis are not, and delivery should not be delayed if chorioamnionitis is diagnosed.

Ultimately, preterm PROM management with a stable mother and fetus at or beyond 34 weeks requires comprehensive counseling of the risks and benefits for both mother and fetus/neonate. A multidisciplinary team that together counsels the patient also may help with this shared decision making.

Term PROM

For patients with term PROM, delivery is recommended. Although a short period of expectant management for 12 to 24 hours is reported as “reasonable,” the risk of infection increases with the length of rupture of membranes. Therefore, induction of labor or CD soon after rupture of membranes is recommended for patients who are GBS positive and is preferred for all others.

VTE prophylaxis in pregnancy: Regimen adjustments, CD strategies, and COVID-19 considerations

Birsner ML, Turrentine M, Pettker CM, et al. ACOG practice advisory: Options for peripartum anticoagulation in areas affected by shortage of unfractionated heparin. March 2020. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/03/options-for-peripartum-anticoagulation-in-areas-affected-by-shortage-of-unfractionated-heparin. Accessed December 8, 2020.

Pacheco LD, Saade G, Metz TD. Society for Maternal-Fetal Medicine Consult Series No. 51: Thromboembolism prophylaxis for cesarean delivery. Am J Obstet Gynecol. 2020;223:B11-B17

Venous thromboembolism (VTE) prophylaxis is a timely topic for a number of reasons. First, a shortage of unfractionated heparin prompted an ACOG Practice Advisory, endorsed by SMFM and the Society for Obstetric Anesthesia and Perinatology, regarding use of low molecular weight heparin (LMWH) in the peripartum period.⁸ In addition, SMFM released updated recommendations for VTE prophylaxis for CD as part of the SMFM Consult Series.⁹ Finally, there is evidence that COVID-19 infection may increase the risk of coagulopathy, leading to consideration of additional VTE prophylaxis for pregnant and postpartum women with COVID-19.

Candidates for prophylaxis

As recommended by the ACOG Practice Bulletin on thromboembolism in pregnancy, women who may require VTE prophylaxis during pregnancy and/or the postpartum period include those with¹⁰:

• VTE diagnosed during pregnancy
• a history of VTE, including during pregnancy or with use of hormonal contraception
• a history of thrombophilia with or without a personal or family history of VTE.

For these patients, LMWH has many advantages over unfractionated heparin, including ease of use and reliability of dosing. It generally is preferred in pregnancy and postpartum (for both prophylactic and therapeutic anticoagulation) by patients and providers.

The Practice Bulletin references a strategy that describes converting LMWH to unfractionated heparin at around 36 weeks’ gestation in preparation for delivery because unfractionated heparin has the advantage of a shorter half-life and the option for anticoagulation reversal with protamine sulfate. In the Practice Advisory, a global shortage of unfractionated heparin and an argument that the above conversion was less about concern for maternal hemorrhage and more about avoiding spinal and epidural hematomas led to the following recommendations for continued use of LMWH through delivery:

• LMWH heparin can be discontinued in a planned fashion prior to scheduled induction of labor or CD (generally 12 hours for prophylactic dosing and 24 hours for intermediate dosing).
• Patients in spontaneous labor may receive neuraxial anesthesia 12 hours after the last prophylactic dose and 24 hours after the last intermediate dose of LMWH.
• Patients who require anticoagulation during pregnancy should be counseled that if they have vaginal bleeding, leakage of fluid, or regular contractions they should be evaluated prior to taking their next dose of anticoagulant.
• In the absence of other complications, delivery should not be before 39 weeks for the indication of anticoagulation requirement alone.

Continue to: Managing VTE risk in CD...

Managing VTE risk in CD

Recognizing that VTE is a major cause of maternal morbidity and mortality, as well as the variety of the published guidelines for VTE prophylaxis after CD, the SMFM Consult Series provides recommendations to assist clinicians caring for postpartum women after CD. As reviewed in the ACOG Practice Bulletin, there are good data to support pharmacologic prophylaxis during pregnancy and the postpartum period for women with a history of VTE or a thrombophilia. Solid evidence is lacking, however, for what to do for women who have a CD without this history but may have other potential risk factors for VTE, such as obesity, preeclampsia, and transfusion requirement. Universal pharmacologic prophylaxis also is not yet supported by evidence. SMFM supports LMWH as the preferred medication in pregnancy and postpartum and provides these additional recommendations:

• All women who have a CD should have sequential compression devices (SCDs) placed prior to surgery and continued until they are ambulatory.
• Women with a history of VTE or thrombophilia without history of VTE should have SCDs and pharmacologic VTE prophylaxis for 6 weeks postpartum.
• Intermediate dosing of LMWH is recommended for patients with class III obesity.
• Institutions should develop patient safety bundles for VTE prophylaxis to identify additional risk factors that may warrant pharmacologic prophylaxis after CD in select patients.

Our approach to patients with COVID-19 infection

At our institution, we recently incorporated a VTE prophylaxis protocol into our electronic medical record that provides risk stratification for each patient. In addition to the above recommendations, our patients may qualify for short-term in-house or longer postpartum prophylaxis depending on risk factors.

A new risk factor in recent months is COVID-19 infection, which appears to increase the risk of coagulopathy, especially in patients with disease severe enough to warrant hospitalization. Given the potential for additive risk in pregnancy, in consult with our medicine colleagues, we have placed some of our more ill hospitalized pregnant patients on a course of prophylactic LMWH both in the hospital and after discharge independent of delivery status or mode of delivery. ●

CASE Fetal anomalies detected on ultrasonography

A 34-year-old woman (G2P1) at 19 weeks’ gestation presented for fetal anatomy ultrasonography evaluation. Ultrasonography demonstrated fetal demise with fetal size less than dates, oligohydramnios, and what appeared to be a full-thickness herniation of the thoracic and abdominal contents. Due to the positioning of the fetus and the oligohydramnios, the fetus appeared to have ectopia cordis and herniated liver and bowel; the bladder was not visualized. The patient was counseled regarding the findings and the suspected diagnosis of pentalogy of Cantrell. After counseling, the patient expressed desire to bury the fetus intact according to her religious custom. She underwent a successful uterine evacuation with misoprostol administration and delivered a nonviable fetus that had a closed thoracic cage without ectopia cordis. Key findings were a very short 2-vessel umbilical cord without coiling that was tethered to the intra-abdominal organs, “pulling” the internal organs out of the abdomen, and lack of an anterior abdominal wall (FIGURE 1). Given these findings, a final diagnosis of body-stalk anomaly was made.

Fetal abdominal wall defects (AWDs) encompass a wide array of congenital defects, although they all involve herniation of 1 or more intra-abdominal content through a ventral abdominal defect.¹ Overall, the estimated incidence of AWDs is approximately 6 per 10,000 births.¹ Gastroschisis and omphalocele are the most common of these defect types.²

The majority of AWDs can be diagnosed during the first trimester of pregnancy via ultrasonography; however, during the first trimester the physiologic midgut herniation resolves by 12 weeks of gestation. It is therefore important to repeat imaging at a later gestational age to confirm the suspicion. Furthermore, the differential diagnosis should include the relatively benign condition of umbilical hernia.

While many AWDs share similarities, they differ significantly in prognosis and management. Early detection is therefore crucial for fetal surveillance, prenatal testing, perinatal planning, and patient counseling (TABLE). In this article, we outline antenatal surveillance and management of AWDs based on recommendations from the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine as well as on our experience and practice.

Gastroschisis is an increasingly prevalent AWD

Gastroschisis is a full-thickness, ventral wall defect that results in bowel evisceration; it typically occurs to the right of the umbilical cord insertion.³ It is one of the most common AWDs and its prevalence has increased in the past few decades, from 2 to 3 cases per 10,000 live births in 1995 to as high as 6 cases per 10,000 live births in 2011.^2,4,5

The cause of gastroschisis remains unclear. The main theory is that there is an ischemic disruption of the closure of the abdominal wall at or near the omphalomesenteric artery or the right umbilical vein.^6,7 In addition, investigators have reported an increased incidence of gastroschisis in mothers exposed to cigarette smoking and certain medications, such as pseudoephedrine, salicylates, ibuprofen, and acetaminophen.^8,9

Continue to: Making the diagnosis...

Prenatal diagnosis using ultrasonography is possible at around 10 weeks of gestation. As previously mentioned, however, physiologic herniation of the midgut must be excluded by performing follow-up imaging at a later gestational age. In our practice, we typically do this at around 16 weeks of gestation.

Ultrasonographic features of gastroschisis include loops of bowel herniating through a small paraumbilical wall defect (usually 2–3 cm) floating in amniotic fluid without a covering membrane⁴ (FIGURE 2). Direct exposure to amniotic fluid causes small bowel inflammation and fibrin deposition, leading to a thickened, echogenic appearance. Polyhydramnios and intra-abdominal bowel dilation have been associated with the presence of intestinal atresia.¹⁰

Management

There is no expert consensus regarding optimal prenatal management of gastroschisis.^11-17 Prenatal care, patient counseling, and delivery planning should be individualized based on the defect and should be determined in a multidisciplinary discussion with specialists in maternal-fetal medicine, neonatology, and pediatric surgery, as necessary. In our practice, if the gastroschisis is isolated and uncomplicated, our generalist obstetricians manage the patient with maternal-fetal medicine consultation, increased fetal surveillance as described below, and delivery at our tertiary care institution.

Our standard practice is to use the initial ultrasonography imaging to evaluate the size and contents of the defect, measure the nuchal translucency, and evaluate for additional abnormalities. Serial ultrasonography monitoring of the fetus is required to assess the size and quality of the herniated intestine, amount of amniotic fluid, and fetal growth.¹⁰

As gastroschisis is a full-thickness defect of the anterior abdominal wall, the abdominal contents are exposed to amniotic fluid. This exposure causes progressive intestinal damage, which can be identified on ultrasonography as bowel thickening and dilation.^12-14 Currently, intestinal thickening and dilation is not considered an indication for delivery as it is assumed that the intestinal damage has already occurred. It is debatable whether delivery around 37 weeks compared with delayed delivery beyond 37 weeks improves outcomes and decreases the stillbirth rate.^11,13 Studies show that neonates delivered prior to 37 weeks have worse outcomes compared with those delivered after 37 weeks.^14,15

Fetal surveillance. As standard practice, we evaluate the fetus at around 16 weeks and then again at around 20 weeks. In the absence of fetal growth restriction, which is associated with 25% of cases,^16,17 our standard practice includes performing serial growth ultrasonography every 3 to 4 weeks starting at 28 weeks and biophysical profiles and nonstress testing weekly starting at 32 weeks. Fetal echocardiography can be offered. However, unlike with omphalocele, which has a high incidence of associated cardiac structural anomalies, gastroschisis has a low incidence of congenital cardiac anomalies, estimated to be between 2.5% and 4%.^18,19

Delivery considerations. Little agreement exists regarding when and how to deliver pregnancies complicated by fetal gastroschisis. While some advocate for induction of labor at 36 to 38 weeks, most infants with gastroschisis can be delivered safely at term via either vaginal or cesarean delivery.^14,15

Delivery timing should consider the clinical picture and incorporate performance on antenatal testing, fetal growth, the size and contents of the gastroschisis, and consultation with maternal-fetal medicine. Fetuses with gastroschisis often have non-reassuring antenatal testing. This can necessitate early delivery, although cesarean delivery should be reserved for obstetric indications, with the caveat that if there is large liver involvement, some pediatric surgeons recommend cesarean delivery due to the risk of hepatic rupture.

Neonate management. The survival rate of gastroschisis is reported to be as high as 91% to 94%.² Morbidity is related to intestinal complications, such as strictures, adhesions, and volvulus.

In the case of simple gastroschisis, when the bowel is in good condition, the treatment method of choice is primary reduction.²⁰ If performed in the operating room, an immediate sutured closure of the defect can be done. The benefits of primary repair include decreased length of stay, fewer intensive care bed days, and less time to achieve full feeds.^20,21 Primary reduction has a reported success rate of 50% to 83%.²² A reduction with a delayed spontaneous closure also can be performed at bedside in the neonatal intensive care unit.²²

For complex gastroschisis, characterized by bowel complications such as inflammation, perforation, ischemia, atresia, necrosis, or volvulus, primary closure may not be possible and reduction may need to be achieved through silo application.^22-25 Additionally, further bowel surgery, such as stoma formation and bowel resection, may be required.²⁵

Continue to: Omphalocele often is associated with abnormal karyotype...

Also known as exomphalos, omphalocele is a relatively common defect, with an estimated prevalence of 2 to 3 cases per 10,000 live births.² In this condition, there is a midline defect in which intra-abdominal contents herniate through the base of the umbilical cord. Omphaloceles are covered by amniotic membranes, making them distinguishable from gastroschisis, which has no covering, and congenital umbilical hernias, which are covered by intact skin and subcutaneous tissue.^26-33

Additionally, in omphalocele the umbilical cord insertion site varies, whereas in gastroschisis the umbilical cord insertion is usually to the right of midline. An omphalocele is often categorized based on whether or not it contains the liver (extracorporeal liver) or only the bowel (intracorporeal liver).

Genetic studies

Approximately 67% to 88% of all pregnancies with omphalocele have an abnormal karyotype and/or associated malformations, including Beckwith-Wiedemann syndrome.³¹ Of the aneuploidies, trisomy 18 is the one most commonly associated with omphalocele, accounting for approximately 62% to 75%, while trisomy 13 accounts for approximately 11% to 24%.^32,33 The presence of other anomalies is strongly associated with poor prognosis, and increased defect size is an independent predictor of neonatal morbidity and mortality, as neonates with large omphaloceles with extracorporeal livers can develop respiratory insufficiency and require more complex surgical repairs. It is interesting, however, that the absence of an extracorporeal liver is associated with a higher risk of aneuploidy than are cases with an intracorporeal liver.³³

We offer chorionic villus sampling or amniocentesis to all patients with omphalocele. If the patient undergoes invasive diagnostic testing, the sample then undergoes karyotyping, chromosomal microarray, and testing for Beckwith-Wiedemann syndrome. If the patient declines diagnostic sampling, we perform a cell-free DNA screening to rule out aneuploidy.

Continue to: Making the diagnosis...

Omphaloceles can be diagnosed via prenatal ultrasonography as early as 11 to 14 weeks’ gestation.²⁶ They are classified based on size, location, and contents of the sac.^26,27 A small omphalocele is defined as a defect less than 5 cm with a sac that may contain a few loops of intestines (FIGURE 3).²⁷ A giant omphalocele is a defect with more than 75% of the liver contained in the sac.²⁹

Location can be epigastric, umbilical, or hypogastric, and both small and giant omphaloceles may have ruptured membranes that will result in exposure of the contained viscera.²⁷ Omphaloceles are associated with such structural anomalies as cardiac, gastrointestinal, genitourinary, diaphragmatic, and neural tube defects. We do not routinely perform magnetic resonance imaging (MRI) for evaluation of omphaloceles, but MRI may be used to help predict postnatal outcomes in the case of giant omphaloceles.²⁶

Management

Our standard practice is to use the initial ultrasonography imaging to evaluate the size and contents of defect, measure the nuchal translucency, and evaluate for additional abnormalities. As in cases of gastroschisis, serial ultrasonography monitoring of the fetus is required to assess the size and quality of the herniated intestine, amount of amniotic fluid, and fetal growth. We typically evaluate the fetus at around 16 weeks and then again at around 20 weeks. In the absence of fetal growth restriction, we recommend serial growth ultrasonography every 3 to 4 weeks starting at 28 weeks and biophysical profiles and nonstress testing weekly starting at 32 weeks. Additionally, we routinely obtain a fetal echocardiogram to rule out cardiac structural abnormalities.

Delivery considerations. Fetuses that do not undergo spontaneous abortion or medical termination of pregnancy often are born at term.²⁶ We recommend expectant management until spontaneous labor, another indication for delivery arises, or at least 39 weeks’ estimated gestational age. There are no evidence-based guidelines for the optimal mode of delivery in fetuses with omphalocele, although we recommend cesarean delivery for fetuses with large defects to avoid postnatal sac rupture and liver damage. Preterm induction of labor is not indicated as infants born preterm have about a 50% mortality rate.^26,27

Children born with isolated omphalocele typically have a good prognosis, with an estimated survival rate of 50% to 90%.^32,33 However, compared to gastroschisis, omphaloceles are often associated with other anomalies.^32,33

Management of omphaloceles depends on the size of the defect. In our institution, our generalist obstetricians manage the standard prenatal care with the addition of increased fetal surveillance and testing, interdisciplinary patient counseling with maternal-fetal medicine, pediatric surgeons, and neonatologists for delivery planning, and delivery is performed at our tertiary care center.

Neonate management. Small omphaloceles are amenable to primary early fascial closure.^26-30 However, attempted primary closure of giant omphaloceles carries significant risks, including abdominal compartment syndrome and postoperative herniation.^29,30 Instead, several options exist for staged surgical closure, in which there are multiple operations prior to final fascial closure, as well as nonoperative delayed closure for management of giant omphaloceles.^29,30

Conservative management of giant omphaloceles has certain benefits, such as earlier first feeds, decreased risk of abdominal compartment syndrome, and lower risk of infection.³⁰ Ruptured omphaloceles can be repaired through primary repair, employment of a synthetic or biologic mesh fascial bridge, or silo placement with delayed closure.²⁸

Body-stalk anomaly: Multiple defects and poor prognosis

Also known as limb body wall complex, body-stalk anomaly is a rare malformation that has a reported prevalence of approximately 0.12 cases per 10,000 births (both live and stillbirths).³⁴ Body-stalk anomaly is characterized by multiple defects, including severe kyphosis or scoliosis, a short or absent umbilical cord, and a large anterior abdominal wall defect.^34-36 This malformation is almost entirely incompatible with life, resulting in abortion or stillbirth.³⁵ Survival is extremely rare and limited to case reports.

While the exact etiology of body-stalk anomaly is unknown, 3 possible causes have been hypothesized: early amnion rupture, vascular compromise, and embryonic dysgenesis.^37-40

Continue to: Making the diagnosis...

Body-stalk anomaly typically can be diagnosed by 10 to 14 weeks’ gestation via ultrasonography.^34-41 We currently follow the diagnostic criteria proposed by Van Allen and colleagues, which requires 2 of the following 3 anomalies³⁴:

• exencephaly/encephalocele with facial clefts
• thoraco- and/or abdominoschisis (midline defect)
• limb defect.

Additional ultrasonographic findings can include the identification of evisceration of the abdominal contents, a short umbilical cord, and increased nuchal thickness.^36,42 During the second and third trimesters, oligohydramnios may be seen.²

Management

Body-stalk anomaly is considered a fatal condition without specific therapeutic interventions. Maternal risks include an increased risk of preterm labor and gestational hypertension.³⁵ Research on body-stalk anomaly has not shown any correlation with patients’ age, fetal sex, or abnormal karyotype, and the reported risk of recurrence for this anomaly is very low.^42,43 Early diagnosis therefore is essential to provide families with information and counseling. Given the poor fetal prognosis, increased maternal risk, and low recurrence rates, mothers can be advised toward elective termination of pregnancy.

Should a patient desire expectant management, care can be provided by generalist obstetricians or care can be transferred to maternal-fetal medicine, with the addition of increased fetal surveillance and testing, interdisciplinary patient counseling with maternal-fetal medicine, pediatric surgeons, and neonatologists for delivery planning; delivery should be performed at a tertiary care center.

Pentalogy of Cantrell: Very rare, with variable prognosis

Pentalogy of Cantrell is characterized by a collection of defects in the midline abdominal wall, lower sternum, anterior diaphragm, diaphragmatic pericardium, and some manifestation of intra-cardiac defect.⁴⁴ It is thought to arise early in gestation due to abnormal differentiation, migration, and fusion of the embryonic mesoderm.⁴⁴ The condition is rare, with an incidence of about 1 in 5.5 million live births.⁴⁵

Making the diagnosis

The diagnosis of pentalogy of Cantrell can be made via prenatal ultrasonography as early as the first trimester, although it is diagnosed more commonly in the second trimester.⁴⁶ Three-dimensional ultrasonography and fetal MRI have been used to confirm the diagnosis.⁴⁷

Management

Typically, corrective operations are performed during the neonatal period, and cases of successful staged and one-stage operations have been reported.⁴⁸ Surgical treatment is determined based on the complexity of the condition and the presence of coexistent heart defects.^49,50 However, very few patients survive surgical repair; mortality rates are estimated at around 50% to 60%, with high postsurgical morbidity risks for those who do survive.⁴⁵

Prognosis varies depending on the type and severity of the associated malformations and intracardiac anomalies.⁴⁶ Patients with partial ectopia cordis and incomplete presentation may have more favorable outcomes, but for patients with severe ectopia cordis, the survival rate is only 5% to 10%.⁴⁷

Depending on the severity of the defects, mothers can be advised toward elective termination of pregnancy. In our institution, prenatal care usually is transferred to the maternal-fetal medicine service, and delivery is planned at our tertiary care institution.

OEIS complex comprises abdominal, pelvic, and spinal defects

Omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex is a congenital malformation syndrome characterized by the combination of midline abdominal and pelvic defects (including omphalocele, exstrophy of the cloaca, and imperforate anus) and spinal defects.⁵¹ The condition’s etiology is unknown but is thought to be multifactorial.^51-53 It is a rare condition, with an incidence of around 1 in 200,000 to 400,000 pregnancies.⁵²

Making the diagnosis

Prenatal diagnosis of OEIS complex can be made as early as the first trimester via ultrasonographic identification of an infraumbilical abdominal wall defect with protruding mass, absent bladder, and spinal defects.⁵² When OEIS complex is suspected, fetal MRI can play a critical role in the diagnosis.

Management

As OEIS complex is rare, there are no evidence-based guidelines for optimal mode and timing of delivery. Cases are individualized based on their specific pathology, and we recommend cesarean delivery for fetuses with large defects to avoid postnatal sac rupture and liver damage.

The prognosis for infants with OEIS complex depends on the spectrum and severity of the structural defects.^52,53 The many surgeries involved in the repair of OEIS have potential complications, such as urogenital and gastrointestinal dysfunction.^52,53 Advances in medical and surgical treatment have resulted in improved survival and quality of life, and survival rates for OEIS complex are now close to 100%.⁵³ While many OEIS patients live with a permanent colostomy, improvements in management mean that more patients are now candidates for gastrointestinal pull-through procedures, which allow for natural bowel control and a higher degree of bowel cleanliness.⁵³

Prenatal care, patient counseling, and delivery planning should be individualized based on the defects present and determined in a multidisciplinary discussion with maternal-fetal medicine, neonatology, and pediatric surgery as necessary. In our institution, prenatal care usually is transferred to the maternal-fetal medicine service, and delivery is planned at our tertiary care institution.

Multidisciplinary team strategy is essential

Based on our experience, when faced with an anterior AWD in utero, prenatal imaging, genetic testing, increased fetal surveillance, and a multidisciplinary team approach improves outcomes. We must emphasize that careful patient counseling is paramount in our practice. ●

Acknowledgement: The authors would like to thank Ashley Tran, BS, for her assistance in the literature review and drafting of this article.

CASE Fetal anomalies detected on ultrasonography

A 34-year-old woman (G2P1) at 19 weeks’ gestation presented for fetal anatomy ultrasonography evaluation. Ultrasonography demonstrated fetal demise with fetal size less than dates, oligohydramnios, and what appeared to be a full-thickness herniation of the thoracic and abdominal contents. Due to the positioning of the fetus and the oligohydramnios, the fetus appeared to have ectopia cordis and herniated liver and bowel; the bladder was not visualized. The patient was counseled regarding the findings and the suspected diagnosis of pentalogy of Cantrell. After counseling, the patient expressed desire to bury the fetus intact according to her religious custom. She underwent a successful uterine evacuation with misoprostol administration and delivered a nonviable fetus that had a closed thoracic cage without ectopia cordis. Key findings were a very short 2-vessel umbilical cord without coiling that was tethered to the intra-abdominal organs, “pulling” the internal organs out of the abdomen, and lack of an anterior abdominal wall (FIGURE 1). Given these findings, a final diagnosis of body-stalk anomaly was made.

Fetal abdominal wall defects (AWDs) encompass a wide array of congenital defects, although they all involve herniation of 1 or more intra-abdominal content through a ventral abdominal defect.¹ Overall, the estimated incidence of AWDs is approximately 6 per 10,000 births.¹ Gastroschisis and omphalocele are the most common of these defect types.²

The majority of AWDs can be diagnosed during the first trimester of pregnancy via ultrasonography; however, during the first trimester the physiologic midgut herniation resolves by 12 weeks of gestation. It is therefore important to repeat imaging at a later gestational age to confirm the suspicion. Furthermore, the differential diagnosis should include the relatively benign condition of umbilical hernia.

While many AWDs share similarities, they differ significantly in prognosis and management. Early detection is therefore crucial for fetal surveillance, prenatal testing, perinatal planning, and patient counseling (TABLE). In this article, we outline antenatal surveillance and management of AWDs based on recommendations from the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine as well as on our experience and practice.

Gastroschisis is an increasingly prevalent AWD

Gastroschisis is a full-thickness, ventral wall defect that results in bowel evisceration; it typically occurs to the right of the umbilical cord insertion.³ It is one of the most common AWDs and its prevalence has increased in the past few decades, from 2 to 3 cases per 10,000 live births in 1995 to as high as 6 cases per 10,000 live births in 2011.^2,4,5

The cause of gastroschisis remains unclear. The main theory is that there is an ischemic disruption of the closure of the abdominal wall at or near the omphalomesenteric artery or the right umbilical vein.^6,7 In addition, investigators have reported an increased incidence of gastroschisis in mothers exposed to cigarette smoking and certain medications, such as pseudoephedrine, salicylates, ibuprofen, and acetaminophen.^8,9

Continue to: Making the diagnosis...

Prenatal diagnosis using ultrasonography is possible at around 10 weeks of gestation. As previously mentioned, however, physiologic herniation of the midgut must be excluded by performing follow-up imaging at a later gestational age. In our practice, we typically do this at around 16 weeks of gestation.

Ultrasonographic features of gastroschisis include loops of bowel herniating through a small paraumbilical wall defect (usually 2–3 cm) floating in amniotic fluid without a covering membrane⁴ (FIGURE 2). Direct exposure to amniotic fluid causes small bowel inflammation and fibrin deposition, leading to a thickened, echogenic appearance. Polyhydramnios and intra-abdominal bowel dilation have been associated with the presence of intestinal atresia.¹⁰

Management

There is no expert consensus regarding optimal prenatal management of gastroschisis.^11-17 Prenatal care, patient counseling, and delivery planning should be individualized based on the defect and should be determined in a multidisciplinary discussion with specialists in maternal-fetal medicine, neonatology, and pediatric surgery, as necessary. In our practice, if the gastroschisis is isolated and uncomplicated, our generalist obstetricians manage the patient with maternal-fetal medicine consultation, increased fetal surveillance as described below, and delivery at our tertiary care institution.

Our standard practice is to use the initial ultrasonography imaging to evaluate the size and contents of the defect, measure the nuchal translucency, and evaluate for additional abnormalities. Serial ultrasonography monitoring of the fetus is required to assess the size and quality of the herniated intestine, amount of amniotic fluid, and fetal growth.¹⁰

As gastroschisis is a full-thickness defect of the anterior abdominal wall, the abdominal contents are exposed to amniotic fluid. This exposure causes progressive intestinal damage, which can be identified on ultrasonography as bowel thickening and dilation.^12-14 Currently, intestinal thickening and dilation is not considered an indication for delivery as it is assumed that the intestinal damage has already occurred. It is debatable whether delivery around 37 weeks compared with delayed delivery beyond 37 weeks improves outcomes and decreases the stillbirth rate.^11,13 Studies show that neonates delivered prior to 37 weeks have worse outcomes compared with those delivered after 37 weeks.^14,15

Fetal surveillance. As standard practice, we evaluate the fetus at around 16 weeks and then again at around 20 weeks. In the absence of fetal growth restriction, which is associated with 25% of cases,^16,17 our standard practice includes performing serial growth ultrasonography every 3 to 4 weeks starting at 28 weeks and biophysical profiles and nonstress testing weekly starting at 32 weeks. Fetal echocardiography can be offered. However, unlike with omphalocele, which has a high incidence of associated cardiac structural anomalies, gastroschisis has a low incidence of congenital cardiac anomalies, estimated to be between 2.5% and 4%.^18,19

Delivery considerations. Little agreement exists regarding when and how to deliver pregnancies complicated by fetal gastroschisis. While some advocate for induction of labor at 36 to 38 weeks, most infants with gastroschisis can be delivered safely at term via either vaginal or cesarean delivery.^14,15

Delivery timing should consider the clinical picture and incorporate performance on antenatal testing, fetal growth, the size and contents of the gastroschisis, and consultation with maternal-fetal medicine. Fetuses with gastroschisis often have non-reassuring antenatal testing. This can necessitate early delivery, although cesarean delivery should be reserved for obstetric indications, with the caveat that if there is large liver involvement, some pediatric surgeons recommend cesarean delivery due to the risk of hepatic rupture.

Neonate management. The survival rate of gastroschisis is reported to be as high as 91% to 94%.² Morbidity is related to intestinal complications, such as strictures, adhesions, and volvulus.

In the case of simple gastroschisis, when the bowel is in good condition, the treatment method of choice is primary reduction.²⁰ If performed in the operating room, an immediate sutured closure of the defect can be done. The benefits of primary repair include decreased length of stay, fewer intensive care bed days, and less time to achieve full feeds.^20,21 Primary reduction has a reported success rate of 50% to 83%.²² A reduction with a delayed spontaneous closure also can be performed at bedside in the neonatal intensive care unit.²²

For complex gastroschisis, characterized by bowel complications such as inflammation, perforation, ischemia, atresia, necrosis, or volvulus, primary closure may not be possible and reduction may need to be achieved through silo application.^22-25 Additionally, further bowel surgery, such as stoma formation and bowel resection, may be required.²⁵

Continue to: Omphalocele often is associated with abnormal karyotype...

Also known as exomphalos, omphalocele is a relatively common defect, with an estimated prevalence of 2 to 3 cases per 10,000 live births.² In this condition, there is a midline defect in which intra-abdominal contents herniate through the base of the umbilical cord. Omphaloceles are covered by amniotic membranes, making them distinguishable from gastroschisis, which has no covering, and congenital umbilical hernias, which are covered by intact skin and subcutaneous tissue.^26-33

Additionally, in omphalocele the umbilical cord insertion site varies, whereas in gastroschisis the umbilical cord insertion is usually to the right of midline. An omphalocele is often categorized based on whether or not it contains the liver (extracorporeal liver) or only the bowel (intracorporeal liver).

Genetic studies

Approximately 67% to 88% of all pregnancies with omphalocele have an abnormal karyotype and/or associated malformations, including Beckwith-Wiedemann syndrome.³¹ Of the aneuploidies, trisomy 18 is the one most commonly associated with omphalocele, accounting for approximately 62% to 75%, while trisomy 13 accounts for approximately 11% to 24%.^32,33 The presence of other anomalies is strongly associated with poor prognosis, and increased defect size is an independent predictor of neonatal morbidity and mortality, as neonates with large omphaloceles with extracorporeal livers can develop respiratory insufficiency and require more complex surgical repairs. It is interesting, however, that the absence of an extracorporeal liver is associated with a higher risk of aneuploidy than are cases with an intracorporeal liver.³³

We offer chorionic villus sampling or amniocentesis to all patients with omphalocele. If the patient undergoes invasive diagnostic testing, the sample then undergoes karyotyping, chromosomal microarray, and testing for Beckwith-Wiedemann syndrome. If the patient declines diagnostic sampling, we perform a cell-free DNA screening to rule out aneuploidy.

Continue to: Making the diagnosis...

Omphaloceles can be diagnosed via prenatal ultrasonography as early as 11 to 14 weeks’ gestation.²⁶ They are classified based on size, location, and contents of the sac.^26,27 A small omphalocele is defined as a defect less than 5 cm with a sac that may contain a few loops of intestines (FIGURE 3).²⁷ A giant omphalocele is a defect with more than 75% of the liver contained in the sac.²⁹

Location can be epigastric, umbilical, or hypogastric, and both small and giant omphaloceles may have ruptured membranes that will result in exposure of the contained viscera.²⁷ Omphaloceles are associated with such structural anomalies as cardiac, gastrointestinal, genitourinary, diaphragmatic, and neural tube defects. We do not routinely perform magnetic resonance imaging (MRI) for evaluation of omphaloceles, but MRI may be used to help predict postnatal outcomes in the case of giant omphaloceles.²⁶

Management

Our standard practice is to use the initial ultrasonography imaging to evaluate the size and contents of defect, measure the nuchal translucency, and evaluate for additional abnormalities. As in cases of gastroschisis, serial ultrasonography monitoring of the fetus is required to assess the size and quality of the herniated intestine, amount of amniotic fluid, and fetal growth. We typically evaluate the fetus at around 16 weeks and then again at around 20 weeks. In the absence of fetal growth restriction, we recommend serial growth ultrasonography every 3 to 4 weeks starting at 28 weeks and biophysical profiles and nonstress testing weekly starting at 32 weeks. Additionally, we routinely obtain a fetal echocardiogram to rule out cardiac structural abnormalities.

Delivery considerations. Fetuses that do not undergo spontaneous abortion or medical termination of pregnancy often are born at term.²⁶ We recommend expectant management until spontaneous labor, another indication for delivery arises, or at least 39 weeks’ estimated gestational age. There are no evidence-based guidelines for the optimal mode of delivery in fetuses with omphalocele, although we recommend cesarean delivery for fetuses with large defects to avoid postnatal sac rupture and liver damage. Preterm induction of labor is not indicated as infants born preterm have about a 50% mortality rate.^26,27

Children born with isolated omphalocele typically have a good prognosis, with an estimated survival rate of 50% to 90%.^32,33 However, compared to gastroschisis, omphaloceles are often associated with other anomalies.^32,33

Management of omphaloceles depends on the size of the defect. In our institution, our generalist obstetricians manage the standard prenatal care with the addition of increased fetal surveillance and testing, interdisciplinary patient counseling with maternal-fetal medicine, pediatric surgeons, and neonatologists for delivery planning, and delivery is performed at our tertiary care center.

Neonate management. Small omphaloceles are amenable to primary early fascial closure.^26-30 However, attempted primary closure of giant omphaloceles carries significant risks, including abdominal compartment syndrome and postoperative herniation.^29,30 Instead, several options exist for staged surgical closure, in which there are multiple operations prior to final fascial closure, as well as nonoperative delayed closure for management of giant omphaloceles.^29,30

Conservative management of giant omphaloceles has certain benefits, such as earlier first feeds, decreased risk of abdominal compartment syndrome, and lower risk of infection.³⁰ Ruptured omphaloceles can be repaired through primary repair, employment of a synthetic or biologic mesh fascial bridge, or silo placement with delayed closure.²⁸

Body-stalk anomaly: Multiple defects and poor prognosis

Also known as limb body wall complex, body-stalk anomaly is a rare malformation that has a reported prevalence of approximately 0.12 cases per 10,000 births (both live and stillbirths).³⁴ Body-stalk anomaly is characterized by multiple defects, including severe kyphosis or scoliosis, a short or absent umbilical cord, and a large anterior abdominal wall defect.^34-36 This malformation is almost entirely incompatible with life, resulting in abortion or stillbirth.³⁵ Survival is extremely rare and limited to case reports.

While the exact etiology of body-stalk anomaly is unknown, 3 possible causes have been hypothesized: early amnion rupture, vascular compromise, and embryonic dysgenesis.^37-40

Continue to: Making the diagnosis...

Body-stalk anomaly typically can be diagnosed by 10 to 14 weeks’ gestation via ultrasonography.^34-41 We currently follow the diagnostic criteria proposed by Van Allen and colleagues, which requires 2 of the following 3 anomalies³⁴:

• exencephaly/encephalocele with facial clefts
• thoraco- and/or abdominoschisis (midline defect)
• limb defect.

Additional ultrasonographic findings can include the identification of evisceration of the abdominal contents, a short umbilical cord, and increased nuchal thickness.^36,42 During the second and third trimesters, oligohydramnios may be seen.²

Management

Body-stalk anomaly is considered a fatal condition without specific therapeutic interventions. Maternal risks include an increased risk of preterm labor and gestational hypertension.³⁵ Research on body-stalk anomaly has not shown any correlation with patients’ age, fetal sex, or abnormal karyotype, and the reported risk of recurrence for this anomaly is very low.^42,43 Early diagnosis therefore is essential to provide families with information and counseling. Given the poor fetal prognosis, increased maternal risk, and low recurrence rates, mothers can be advised toward elective termination of pregnancy.

Should a patient desire expectant management, care can be provided by generalist obstetricians or care can be transferred to maternal-fetal medicine, with the addition of increased fetal surveillance and testing, interdisciplinary patient counseling with maternal-fetal medicine, pediatric surgeons, and neonatologists for delivery planning; delivery should be performed at a tertiary care center.

Pentalogy of Cantrell: Very rare, with variable prognosis

Pentalogy of Cantrell is characterized by a collection of defects in the midline abdominal wall, lower sternum, anterior diaphragm, diaphragmatic pericardium, and some manifestation of intra-cardiac defect.⁴⁴ It is thought to arise early in gestation due to abnormal differentiation, migration, and fusion of the embryonic mesoderm.⁴⁴ The condition is rare, with an incidence of about 1 in 5.5 million live births.⁴⁵

Making the diagnosis

The diagnosis of pentalogy of Cantrell can be made via prenatal ultrasonography as early as the first trimester, although it is diagnosed more commonly in the second trimester.⁴⁶ Three-dimensional ultrasonography and fetal MRI have been used to confirm the diagnosis.⁴⁷

Management

Typically, corrective operations are performed during the neonatal period, and cases of successful staged and one-stage operations have been reported.⁴⁸ Surgical treatment is determined based on the complexity of the condition and the presence of coexistent heart defects.^49,50 However, very few patients survive surgical repair; mortality rates are estimated at around 50% to 60%, with high postsurgical morbidity risks for those who do survive.⁴⁵

Prognosis varies depending on the type and severity of the associated malformations and intracardiac anomalies.⁴⁶ Patients with partial ectopia cordis and incomplete presentation may have more favorable outcomes, but for patients with severe ectopia cordis, the survival rate is only 5% to 10%.⁴⁷

Depending on the severity of the defects, mothers can be advised toward elective termination of pregnancy. In our institution, prenatal care usually is transferred to the maternal-fetal medicine service, and delivery is planned at our tertiary care institution.

OEIS complex comprises abdominal, pelvic, and spinal defects

Omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex is a congenital malformation syndrome characterized by the combination of midline abdominal and pelvic defects (including omphalocele, exstrophy of the cloaca, and imperforate anus) and spinal defects.⁵¹ The condition’s etiology is unknown but is thought to be multifactorial.^51-53 It is a rare condition, with an incidence of around 1 in 200,000 to 400,000 pregnancies.⁵²

Making the diagnosis

Prenatal diagnosis of OEIS complex can be made as early as the first trimester via ultrasonographic identification of an infraumbilical abdominal wall defect with protruding mass, absent bladder, and spinal defects.⁵² When OEIS complex is suspected, fetal MRI can play a critical role in the diagnosis.

Management

As OEIS complex is rare, there are no evidence-based guidelines for optimal mode and timing of delivery. Cases are individualized based on their specific pathology, and we recommend cesarean delivery for fetuses with large defects to avoid postnatal sac rupture and liver damage.

The prognosis for infants with OEIS complex depends on the spectrum and severity of the structural defects.^52,53 The many surgeries involved in the repair of OEIS have potential complications, such as urogenital and gastrointestinal dysfunction.^52,53 Advances in medical and surgical treatment have resulted in improved survival and quality of life, and survival rates for OEIS complex are now close to 100%.⁵³ While many OEIS patients live with a permanent colostomy, improvements in management mean that more patients are now candidates for gastrointestinal pull-through procedures, which allow for natural bowel control and a higher degree of bowel cleanliness.⁵³

Prenatal care, patient counseling, and delivery planning should be individualized based on the defects present and determined in a multidisciplinary discussion with maternal-fetal medicine, neonatology, and pediatric surgery as necessary. In our institution, prenatal care usually is transferred to the maternal-fetal medicine service, and delivery is planned at our tertiary care institution.

Multidisciplinary team strategy is essential

Based on our experience, when faced with an anterior AWD in utero, prenatal imaging, genetic testing, increased fetal surveillance, and a multidisciplinary team approach improves outcomes. We must emphasize that careful patient counseling is paramount in our practice. ●

Acknowledgement: The authors would like to thank Ashley Tran, BS, for her assistance in the literature review and drafting of this article.

CASE Fetal anomalies detected on ultrasonography

A 34-year-old woman (G2P1) at 19 weeks’ gestation presented for fetal anatomy ultrasonography evaluation. Ultrasonography demonstrated fetal demise with fetal size less than dates, oligohydramnios, and what appeared to be a full-thickness herniation of the thoracic and abdominal contents. Due to the positioning of the fetus and the oligohydramnios, the fetus appeared to have ectopia cordis and herniated liver and bowel; the bladder was not visualized. The patient was counseled regarding the findings and the suspected diagnosis of pentalogy of Cantrell. After counseling, the patient expressed desire to bury the fetus intact according to her religious custom. She underwent a successful uterine evacuation with misoprostol administration and delivered a nonviable fetus that had a closed thoracic cage without ectopia cordis. Key findings were a very short 2-vessel umbilical cord without coiling that was tethered to the intra-abdominal organs, “pulling” the internal organs out of the abdomen, and lack of an anterior abdominal wall (FIGURE 1). Given these findings, a final diagnosis of body-stalk anomaly was made.

Fetal abdominal wall defects (AWDs) encompass a wide array of congenital defects, although they all involve herniation of 1 or more intra-abdominal content through a ventral abdominal defect.¹ Overall, the estimated incidence of AWDs is approximately 6 per 10,000 births.¹ Gastroschisis and omphalocele are the most common of these defect types.²

The majority of AWDs can be diagnosed during the first trimester of pregnancy via ultrasonography; however, during the first trimester the physiologic midgut herniation resolves by 12 weeks of gestation. It is therefore important to repeat imaging at a later gestational age to confirm the suspicion. Furthermore, the differential diagnosis should include the relatively benign condition of umbilical hernia.

While many AWDs share similarities, they differ significantly in prognosis and management. Early detection is therefore crucial for fetal surveillance, prenatal testing, perinatal planning, and patient counseling (TABLE). In this article, we outline antenatal surveillance and management of AWDs based on recommendations from the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine as well as on our experience and practice.

Gastroschisis is an increasingly prevalent AWD

Gastroschisis is a full-thickness, ventral wall defect that results in bowel evisceration; it typically occurs to the right of the umbilical cord insertion.³ It is one of the most common AWDs and its prevalence has increased in the past few decades, from 2 to 3 cases per 10,000 live births in 1995 to as high as 6 cases per 10,000 live births in 2011.^2,4,5

The cause of gastroschisis remains unclear. The main theory is that there is an ischemic disruption of the closure of the abdominal wall at or near the omphalomesenteric artery or the right umbilical vein.^6,7 In addition, investigators have reported an increased incidence of gastroschisis in mothers exposed to cigarette smoking and certain medications, such as pseudoephedrine, salicylates, ibuprofen, and acetaminophen.^8,9

Continue to: Making the diagnosis...

Prenatal diagnosis using ultrasonography is possible at around 10 weeks of gestation. As previously mentioned, however, physiologic herniation of the midgut must be excluded by performing follow-up imaging at a later gestational age. In our practice, we typically do this at around 16 weeks of gestation.

Ultrasonographic features of gastroschisis include loops of bowel herniating through a small paraumbilical wall defect (usually 2–3 cm) floating in amniotic fluid without a covering membrane⁴ (FIGURE 2). Direct exposure to amniotic fluid causes small bowel inflammation and fibrin deposition, leading to a thickened, echogenic appearance. Polyhydramnios and intra-abdominal bowel dilation have been associated with the presence of intestinal atresia.¹⁰

Management

There is no expert consensus regarding optimal prenatal management of gastroschisis.^11-17 Prenatal care, patient counseling, and delivery planning should be individualized based on the defect and should be determined in a multidisciplinary discussion with specialists in maternal-fetal medicine, neonatology, and pediatric surgery, as necessary. In our practice, if the gastroschisis is isolated and uncomplicated, our generalist obstetricians manage the patient with maternal-fetal medicine consultation, increased fetal surveillance as described below, and delivery at our tertiary care institution.

Our standard practice is to use the initial ultrasonography imaging to evaluate the size and contents of the defect, measure the nuchal translucency, and evaluate for additional abnormalities. Serial ultrasonography monitoring of the fetus is required to assess the size and quality of the herniated intestine, amount of amniotic fluid, and fetal growth.¹⁰

As gastroschisis is a full-thickness defect of the anterior abdominal wall, the abdominal contents are exposed to amniotic fluid. This exposure causes progressive intestinal damage, which can be identified on ultrasonography as bowel thickening and dilation.^12-14 Currently, intestinal thickening and dilation is not considered an indication for delivery as it is assumed that the intestinal damage has already occurred. It is debatable whether delivery around 37 weeks compared with delayed delivery beyond 37 weeks improves outcomes and decreases the stillbirth rate.^11,13 Studies show that neonates delivered prior to 37 weeks have worse outcomes compared with those delivered after 37 weeks.^14,15

Fetal surveillance. As standard practice, we evaluate the fetus at around 16 weeks and then again at around 20 weeks. In the absence of fetal growth restriction, which is associated with 25% of cases,^16,17 our standard practice includes performing serial growth ultrasonography every 3 to 4 weeks starting at 28 weeks and biophysical profiles and nonstress testing weekly starting at 32 weeks. Fetal echocardiography can be offered. However, unlike with omphalocele, which has a high incidence of associated cardiac structural anomalies, gastroschisis has a low incidence of congenital cardiac anomalies, estimated to be between 2.5% and 4%.^18,19

Delivery considerations. Little agreement exists regarding when and how to deliver pregnancies complicated by fetal gastroschisis. While some advocate for induction of labor at 36 to 38 weeks, most infants with gastroschisis can be delivered safely at term via either vaginal or cesarean delivery.^14,15

Delivery timing should consider the clinical picture and incorporate performance on antenatal testing, fetal growth, the size and contents of the gastroschisis, and consultation with maternal-fetal medicine. Fetuses with gastroschisis often have non-reassuring antenatal testing. This can necessitate early delivery, although cesarean delivery should be reserved for obstetric indications, with the caveat that if there is large liver involvement, some pediatric surgeons recommend cesarean delivery due to the risk of hepatic rupture.

Neonate management. The survival rate of gastroschisis is reported to be as high as 91% to 94%.² Morbidity is related to intestinal complications, such as strictures, adhesions, and volvulus.

In the case of simple gastroschisis, when the bowel is in good condition, the treatment method of choice is primary reduction.²⁰ If performed in the operating room, an immediate sutured closure of the defect can be done. The benefits of primary repair include decreased length of stay, fewer intensive care bed days, and less time to achieve full feeds.^20,21 Primary reduction has a reported success rate of 50% to 83%.²² A reduction with a delayed spontaneous closure also can be performed at bedside in the neonatal intensive care unit.²²

For complex gastroschisis, characterized by bowel complications such as inflammation, perforation, ischemia, atresia, necrosis, or volvulus, primary closure may not be possible and reduction may need to be achieved through silo application.^22-25 Additionally, further bowel surgery, such as stoma formation and bowel resection, may be required.²⁵

Continue to: Omphalocele often is associated with abnormal karyotype...

Also known as exomphalos, omphalocele is a relatively common defect, with an estimated prevalence of 2 to 3 cases per 10,000 live births.² In this condition, there is a midline defect in which intra-abdominal contents herniate through the base of the umbilical cord. Omphaloceles are covered by amniotic membranes, making them distinguishable from gastroschisis, which has no covering, and congenital umbilical hernias, which are covered by intact skin and subcutaneous tissue.^26-33

Additionally, in omphalocele the umbilical cord insertion site varies, whereas in gastroschisis the umbilical cord insertion is usually to the right of midline. An omphalocele is often categorized based on whether or not it contains the liver (extracorporeal liver) or only the bowel (intracorporeal liver).

Genetic studies

Approximately 67% to 88% of all pregnancies with omphalocele have an abnormal karyotype and/or associated malformations, including Beckwith-Wiedemann syndrome.³¹ Of the aneuploidies, trisomy 18 is the one most commonly associated with omphalocele, accounting for approximately 62% to 75%, while trisomy 13 accounts for approximately 11% to 24%.^32,33 The presence of other anomalies is strongly associated with poor prognosis, and increased defect size is an independent predictor of neonatal morbidity and mortality, as neonates with large omphaloceles with extracorporeal livers can develop respiratory insufficiency and require more complex surgical repairs. It is interesting, however, that the absence of an extracorporeal liver is associated with a higher risk of aneuploidy than are cases with an intracorporeal liver.³³

We offer chorionic villus sampling or amniocentesis to all patients with omphalocele. If the patient undergoes invasive diagnostic testing, the sample then undergoes karyotyping, chromosomal microarray, and testing for Beckwith-Wiedemann syndrome. If the patient declines diagnostic sampling, we perform a cell-free DNA screening to rule out aneuploidy.

Continue to: Making the diagnosis...

Omphaloceles can be diagnosed via prenatal ultrasonography as early as 11 to 14 weeks’ gestation.²⁶ They are classified based on size, location, and contents of the sac.^26,27 A small omphalocele is defined as a defect less than 5 cm with a sac that may contain a few loops of intestines (FIGURE 3).²⁷ A giant omphalocele is a defect with more than 75% of the liver contained in the sac.²⁹

Location can be epigastric, umbilical, or hypogastric, and both small and giant omphaloceles may have ruptured membranes that will result in exposure of the contained viscera.²⁷ Omphaloceles are associated with such structural anomalies as cardiac, gastrointestinal, genitourinary, diaphragmatic, and neural tube defects. We do not routinely perform magnetic resonance imaging (MRI) for evaluation of omphaloceles, but MRI may be used to help predict postnatal outcomes in the case of giant omphaloceles.²⁶

Management

Our standard practice is to use the initial ultrasonography imaging to evaluate the size and contents of defect, measure the nuchal translucency, and evaluate for additional abnormalities. As in cases of gastroschisis, serial ultrasonography monitoring of the fetus is required to assess the size and quality of the herniated intestine, amount of amniotic fluid, and fetal growth. We typically evaluate the fetus at around 16 weeks and then again at around 20 weeks. In the absence of fetal growth restriction, we recommend serial growth ultrasonography every 3 to 4 weeks starting at 28 weeks and biophysical profiles and nonstress testing weekly starting at 32 weeks. Additionally, we routinely obtain a fetal echocardiogram to rule out cardiac structural abnormalities.

Delivery considerations. Fetuses that do not undergo spontaneous abortion or medical termination of pregnancy often are born at term.²⁶ We recommend expectant management until spontaneous labor, another indication for delivery arises, or at least 39 weeks’ estimated gestational age. There are no evidence-based guidelines for the optimal mode of delivery in fetuses with omphalocele, although we recommend cesarean delivery for fetuses with large defects to avoid postnatal sac rupture and liver damage. Preterm induction of labor is not indicated as infants born preterm have about a 50% mortality rate.^26,27

Children born with isolated omphalocele typically have a good prognosis, with an estimated survival rate of 50% to 90%.^32,33 However, compared to gastroschisis, omphaloceles are often associated with other anomalies.^32,33

Management of omphaloceles depends on the size of the defect. In our institution, our generalist obstetricians manage the standard prenatal care with the addition of increased fetal surveillance and testing, interdisciplinary patient counseling with maternal-fetal medicine, pediatric surgeons, and neonatologists for delivery planning, and delivery is performed at our tertiary care center.

Neonate management. Small omphaloceles are amenable to primary early fascial closure.^26-30 However, attempted primary closure of giant omphaloceles carries significant risks, including abdominal compartment syndrome and postoperative herniation.^29,30 Instead, several options exist for staged surgical closure, in which there are multiple operations prior to final fascial closure, as well as nonoperative delayed closure for management of giant omphaloceles.^29,30

Conservative management of giant omphaloceles has certain benefits, such as earlier first feeds, decreased risk of abdominal compartment syndrome, and lower risk of infection.³⁰ Ruptured omphaloceles can be repaired through primary repair, employment of a synthetic or biologic mesh fascial bridge, or silo placement with delayed closure.²⁸

Body-stalk anomaly: Multiple defects and poor prognosis

Also known as limb body wall complex, body-stalk anomaly is a rare malformation that has a reported prevalence of approximately 0.12 cases per 10,000 births (both live and stillbirths).³⁴ Body-stalk anomaly is characterized by multiple defects, including severe kyphosis or scoliosis, a short or absent umbilical cord, and a large anterior abdominal wall defect.^34-36 This malformation is almost entirely incompatible with life, resulting in abortion or stillbirth.³⁵ Survival is extremely rare and limited to case reports.

While the exact etiology of body-stalk anomaly is unknown, 3 possible causes have been hypothesized: early amnion rupture, vascular compromise, and embryonic dysgenesis.^37-40

Continue to: Making the diagnosis...

Body-stalk anomaly typically can be diagnosed by 10 to 14 weeks’ gestation via ultrasonography.^34-41 We currently follow the diagnostic criteria proposed by Van Allen and colleagues, which requires 2 of the following 3 anomalies³⁴:

• exencephaly/encephalocele with facial clefts
• thoraco- and/or abdominoschisis (midline defect)
• limb defect.

Additional ultrasonographic findings can include the identification of evisceration of the abdominal contents, a short umbilical cord, and increased nuchal thickness.^36,42 During the second and third trimesters, oligohydramnios may be seen.²

Management

Body-stalk anomaly is considered a fatal condition without specific therapeutic interventions. Maternal risks include an increased risk of preterm labor and gestational hypertension.³⁵ Research on body-stalk anomaly has not shown any correlation with patients’ age, fetal sex, or abnormal karyotype, and the reported risk of recurrence for this anomaly is very low.^42,43 Early diagnosis therefore is essential to provide families with information and counseling. Given the poor fetal prognosis, increased maternal risk, and low recurrence rates, mothers can be advised toward elective termination of pregnancy.

Should a patient desire expectant management, care can be provided by generalist obstetricians or care can be transferred to maternal-fetal medicine, with the addition of increased fetal surveillance and testing, interdisciplinary patient counseling with maternal-fetal medicine, pediatric surgeons, and neonatologists for delivery planning; delivery should be performed at a tertiary care center.

Pentalogy of Cantrell: Very rare, with variable prognosis

Pentalogy of Cantrell is characterized by a collection of defects in the midline abdominal wall, lower sternum, anterior diaphragm, diaphragmatic pericardium, and some manifestation of intra-cardiac defect.⁴⁴ It is thought to arise early in gestation due to abnormal differentiation, migration, and fusion of the embryonic mesoderm.⁴⁴ The condition is rare, with an incidence of about 1 in 5.5 million live births.⁴⁵

Making the diagnosis

The diagnosis of pentalogy of Cantrell can be made via prenatal ultrasonography as early as the first trimester, although it is diagnosed more commonly in the second trimester.⁴⁶ Three-dimensional ultrasonography and fetal MRI have been used to confirm the diagnosis.⁴⁷

Management

Typically, corrective operations are performed during the neonatal period, and cases of successful staged and one-stage operations have been reported.⁴⁸ Surgical treatment is determined based on the complexity of the condition and the presence of coexistent heart defects.^49,50 However, very few patients survive surgical repair; mortality rates are estimated at around 50% to 60%, with high postsurgical morbidity risks for those who do survive.⁴⁵

Prognosis varies depending on the type and severity of the associated malformations and intracardiac anomalies.⁴⁶ Patients with partial ectopia cordis and incomplete presentation may have more favorable outcomes, but for patients with severe ectopia cordis, the survival rate is only 5% to 10%.⁴⁷

Depending on the severity of the defects, mothers can be advised toward elective termination of pregnancy. In our institution, prenatal care usually is transferred to the maternal-fetal medicine service, and delivery is planned at our tertiary care institution.

OEIS complex comprises abdominal, pelvic, and spinal defects

Omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex is a congenital malformation syndrome characterized by the combination of midline abdominal and pelvic defects (including omphalocele, exstrophy of the cloaca, and imperforate anus) and spinal defects.⁵¹ The condition’s etiology is unknown but is thought to be multifactorial.^51-53 It is a rare condition, with an incidence of around 1 in 200,000 to 400,000 pregnancies.⁵²

Making the diagnosis

Prenatal diagnosis of OEIS complex can be made as early as the first trimester via ultrasonographic identification of an infraumbilical abdominal wall defect with protruding mass, absent bladder, and spinal defects.⁵² When OEIS complex is suspected, fetal MRI can play a critical role in the diagnosis.

Management

As OEIS complex is rare, there are no evidence-based guidelines for optimal mode and timing of delivery. Cases are individualized based on their specific pathology, and we recommend cesarean delivery for fetuses with large defects to avoid postnatal sac rupture and liver damage.

The prognosis for infants with OEIS complex depends on the spectrum and severity of the structural defects.^52,53 The many surgeries involved in the repair of OEIS have potential complications, such as urogenital and gastrointestinal dysfunction.^52,53 Advances in medical and surgical treatment have resulted in improved survival and quality of life, and survival rates for OEIS complex are now close to 100%.⁵³ While many OEIS patients live with a permanent colostomy, improvements in management mean that more patients are now candidates for gastrointestinal pull-through procedures, which allow for natural bowel control and a higher degree of bowel cleanliness.⁵³

Prenatal care, patient counseling, and delivery planning should be individualized based on the defects present and determined in a multidisciplinary discussion with maternal-fetal medicine, neonatology, and pediatric surgery as necessary. In our institution, prenatal care usually is transferred to the maternal-fetal medicine service, and delivery is planned at our tertiary care institution.

Multidisciplinary team strategy is essential

Based on our experience, when faced with an anterior AWD in utero, prenatal imaging, genetic testing, increased fetal surveillance, and a multidisciplinary team approach improves outcomes. We must emphasize that careful patient counseling is paramount in our practice. ●

Acknowledgement: The authors would like to thank Ashley Tran, BS, for her assistance in the literature review and drafting of this article.

What Are Essential Oils?

Essential oils are aromatic volatile oils produced by medicinal plants that give them their distinct flavors and aromas. They are extracted using a variety of different techniques, such as microwave-assisted extraction, headspace extraction, and the most commonly employed hydrodistillation.¹ Different parts of the plant are used for the specific oils; the shoots and leaves of Origanum vulgare are used for oregano oil, whereas the skins of Citrus limonum are used for lemon oil.² Historically, essential oils have been used for cooking, food preservation, perfume, and medicine.^3,4

Historical Uses for Essential Oils

Essential oils and their intact medicinal plants were among the first medicines widely available to the ancient world. The Ancient Greeks used topical and oral oregano as a cure-all for ailments including wounds, sore muscles, and diarrhea. Because of its use as a cure-all medicine, it remains a popular folk remedy in parts of Europe today.³ Lavender also has a long history of being a cure-all plant and oil. Some of the many claims behind this flower include treatment of burns, insect bites, parasites, muscle spasms, nausea, and anxiety/depression.⁵ With an extensive list of historical uses, many essential oils are being researched to determine if their acclaimed qualities have quantifiable properties.

Science Behind the Belief

In vitro experiments with oregano (O vulgare) have demonstrated notable antifungal and antimicrobial effects.⁶ Gas chromatographic analysis of the oil shows much of it is composed of phenolic monoterpenes, such as thymol and carvacrol. They exhibit strong antifungal effects with a slightly stronger effect on the dermatophyte Trichophyton rubrum over other yeast species such as Candida.^7,8 The full effect of the monoterpenes on fungi is not completely understood, but early data show it has a strong affinity for the ergosterol used in the cell-wall synthesis. Other effects demonstrated in in vitro studies include the ability to block drug efflux pumps, biofilm formation, cellular communication among bacteria, and mycotoxin production.⁹

A double-blind, randomized trial by Akhondzadeh et al¹⁰ demonstrated lavender (Lavandula officinalis) to have a mild antidepressant quality but a noticeably more potent effect when combined with imipramine. The effects of the lavender with imipramine were stronger and provided earlier improvement than imipramine alone for treatment of mild to moderate depression. The team concluded that lavender may be an effective adjunct therapy in treating depression.¹⁰

In a study by Mori et al,¹¹ full-thickness circular wounds were made in rats and treated with either lavender oil (L officinalis), nothing, or a control oil. With the lavender oil being at only 1% solution, the wounds treated with lavender oil demonstrated earlier closure than the other 2 groups of wounds, where no major difference was noted. On cellular analysis, it was seen that the lavender had increased the rate of granulation as well as expression of types I and III collagen. The most striking result was the large expression of transforming growth factor β seen in the lavender group compared to the others. The final thoughts on this experiment were that lavender may provide new approaches to wound care in the future.¹¹

Potential Problems With Purity

One major concern raised about essential oils is their purity and the fidelity of their chemical composition. The specific aromatic chemicals in each essential oil are maintained for each species, but the proportions of each change even with the time of year.¹² Gas chromatograph analysis of the same oil distilled with different techniques showed that the proportions of aromatic chemicals varied with technique. However, the major constituents of the oil remained present in large quantities, just at different percentages.¹ Even using the same distillation technique for different time periods can greatly affect the yield and composition of the oil. Although the percentage of each aromatic compound can be affected by distillation times, the antioxidant and antimicrobial effects of the oil remain constant regardless of these variables.² There is clearly a lack in standardization in essential oil production, which may not be an issue for its use in complementary medicine if its properties are maintained regardless.

Safety Concerns and Regulations

With essential oils being a natural cure for everyday ailments, some people are turning first to oils for every cut and bruise. The danger in these natural cures is that essential oils can cause several types of dermatitis and allergic reactions. The development of allergies to essential oils is at an even higher risk, considering people frequently put them on wounds and rashes where the skin barrier is already weakened. Many essential oils fall into the fragrance category in patch tests, negating the widely circulating blogger and online reports that essential oils cannot cause allergies.

Some of the oils, although regarded safe by the US Food and Drug Administration for consumption, can cause dermatitis from simple contact or with sun exposure.¹³ Members of the citrus family are notorious for the phytophotodermatitis reaction, which can leave hyperpigmented scarring after exposure of the oils to sunlight.¹⁴ Most companies that sell essential oils are aware of this reaction and include it in the warning labels.

The legal problem with selling and classifying essential oils is that the US Food and Drug Administration requires products intended for treatment to be labeled as drugs, which hinders their sales on the open market.¹³ It all boils down to intended use, so some companies sell the oils under a food or fragrance classification with vague instructions on how to use said oil for medicinal purposes, which leads to lack of supervision, anecdotal cures, and false health claims. One company claims in their safety guide for topical applications of their oils that “[i]f a rash occurs, this may be a sign of detoxification.”¹⁵ If essential oils had only minimal absorption topically, their safety would be less concerning, but this does not appear to be the case.

Absorption and Systemics

The effects of essential oils on the skin is one aspect of their use to be studied; another is the more systemic effects from absorption through the skin. Most essential oils used in small quantities for fragrance in over-the-counter lotions prove only to be an issue for allergens in sensitive patient groups. However, topical applications of essential oils in their pure concentrated form get absorbed into the skin faster than if used with a carrier oil, emulsion, or solvent.¹⁶ For most minor uses of essential oils, the body can detoxify absorbed chemicals the same way it does when a person eats the plants the oils came from (eg, basil essential oils leaching from the leaves into a tomato sauce). A possible danger of the oils’ systemic properties lies in the pregnant patient population who use essential oils thinking that natural is safe.

Many essential oils, such as lavender (L officinalis), exhibit hormonal mimicry with phytoestrogens and can produce emmenagogue (increasing menstrual flow) effects in women. Other oils, such as those of nutmeg (Myristica fragrans) and myrrh (Commiphora myrrha), can have abortifacient effects. These natural essential oils can lead to unintended health risks for mother and baby.¹⁷ With implications this serious, many essential oil companies put pregnancy warnings on most if not all of their products, but pregnant patients may not always note the risk.

Conclusion

Essential oils are not the newest medical fad. They outdate every drug on the market and were used by some of the first physicians in history. It is important to continue research into the antimicrobial effects of essential oils, as they may hold the secret to treatment options with the continued rise of multidrug-resistant organisms. The danger of these oils lies not in their hidden potential but in the belief that natural things are safe. A few animal studies have been performed, but little is known about the full effects of essential oils in humans. Patients need to be educated that these are not panaceas with freedom from side effects and that treatment options backed by the scientific method should be their first choice under the supervision of trained physicians. The Table outlines the uses and side effects of the essential oils discussed here.

What Are Essential Oils?

Essential oils are aromatic volatile oils produced by medicinal plants that give them their distinct flavors and aromas. They are extracted using a variety of different techniques, such as microwave-assisted extraction, headspace extraction, and the most commonly employed hydrodistillation.¹ Different parts of the plant are used for the specific oils; the shoots and leaves of Origanum vulgare are used for oregano oil, whereas the skins of Citrus limonum are used for lemon oil.² Historically, essential oils have been used for cooking, food preservation, perfume, and medicine.^3,4

Historical Uses for Essential Oils

Essential oils and their intact medicinal plants were among the first medicines widely available to the ancient world. The Ancient Greeks used topical and oral oregano as a cure-all for ailments including wounds, sore muscles, and diarrhea. Because of its use as a cure-all medicine, it remains a popular folk remedy in parts of Europe today.³ Lavender also has a long history of being a cure-all plant and oil. Some of the many claims behind this flower include treatment of burns, insect bites, parasites, muscle spasms, nausea, and anxiety/depression.⁵ With an extensive list of historical uses, many essential oils are being researched to determine if their acclaimed qualities have quantifiable properties.

Science Behind the Belief

In vitro experiments with oregano (O vulgare) have demonstrated notable antifungal and antimicrobial effects.⁶ Gas chromatographic analysis of the oil shows much of it is composed of phenolic monoterpenes, such as thymol and carvacrol. They exhibit strong antifungal effects with a slightly stronger effect on the dermatophyte Trichophyton rubrum over other yeast species such as Candida.^7,8 The full effect of the monoterpenes on fungi is not completely understood, but early data show it has a strong affinity for the ergosterol used in the cell-wall synthesis. Other effects demonstrated in in vitro studies include the ability to block drug efflux pumps, biofilm formation, cellular communication among bacteria, and mycotoxin production.⁹

A double-blind, randomized trial by Akhondzadeh et al¹⁰ demonstrated lavender (Lavandula officinalis) to have a mild antidepressant quality but a noticeably more potent effect when combined with imipramine. The effects of the lavender with imipramine were stronger and provided earlier improvement than imipramine alone for treatment of mild to moderate depression. The team concluded that lavender may be an effective adjunct therapy in treating depression.¹⁰

In a study by Mori et al,¹¹ full-thickness circular wounds were made in rats and treated with either lavender oil (L officinalis), nothing, or a control oil. With the lavender oil being at only 1% solution, the wounds treated with lavender oil demonstrated earlier closure than the other 2 groups of wounds, where no major difference was noted. On cellular analysis, it was seen that the lavender had increased the rate of granulation as well as expression of types I and III collagen. The most striking result was the large expression of transforming growth factor β seen in the lavender group compared to the others. The final thoughts on this experiment were that lavender may provide new approaches to wound care in the future.¹¹

Potential Problems With Purity

One major concern raised about essential oils is their purity and the fidelity of their chemical composition. The specific aromatic chemicals in each essential oil are maintained for each species, but the proportions of each change even with the time of year.¹² Gas chromatograph analysis of the same oil distilled with different techniques showed that the proportions of aromatic chemicals varied with technique. However, the major constituents of the oil remained present in large quantities, just at different percentages.¹ Even using the same distillation technique for different time periods can greatly affect the yield and composition of the oil. Although the percentage of each aromatic compound can be affected by distillation times, the antioxidant and antimicrobial effects of the oil remain constant regardless of these variables.² There is clearly a lack in standardization in essential oil production, which may not be an issue for its use in complementary medicine if its properties are maintained regardless.

Safety Concerns and Regulations

With essential oils being a natural cure for everyday ailments, some people are turning first to oils for every cut and bruise. The danger in these natural cures is that essential oils can cause several types of dermatitis and allergic reactions. The development of allergies to essential oils is at an even higher risk, considering people frequently put them on wounds and rashes where the skin barrier is already weakened. Many essential oils fall into the fragrance category in patch tests, negating the widely circulating blogger and online reports that essential oils cannot cause allergies.

Some of the oils, although regarded safe by the US Food and Drug Administration for consumption, can cause dermatitis from simple contact or with sun exposure.¹³ Members of the citrus family are notorious for the phytophotodermatitis reaction, which can leave hyperpigmented scarring after exposure of the oils to sunlight.¹⁴ Most companies that sell essential oils are aware of this reaction and include it in the warning labels.

The legal problem with selling and classifying essential oils is that the US Food and Drug Administration requires products intended for treatment to be labeled as drugs, which hinders their sales on the open market.¹³ It all boils down to intended use, so some companies sell the oils under a food or fragrance classification with vague instructions on how to use said oil for medicinal purposes, which leads to lack of supervision, anecdotal cures, and false health claims. One company claims in their safety guide for topical applications of their oils that “[i]f a rash occurs, this may be a sign of detoxification.”¹⁵ If essential oils had only minimal absorption topically, their safety would be less concerning, but this does not appear to be the case.

Absorption and Systemics

The effects of essential oils on the skin is one aspect of their use to be studied; another is the more systemic effects from absorption through the skin. Most essential oils used in small quantities for fragrance in over-the-counter lotions prove only to be an issue for allergens in sensitive patient groups. However, topical applications of essential oils in their pure concentrated form get absorbed into the skin faster than if used with a carrier oil, emulsion, or solvent.¹⁶ For most minor uses of essential oils, the body can detoxify absorbed chemicals the same way it does when a person eats the plants the oils came from (eg, basil essential oils leaching from the leaves into a tomato sauce). A possible danger of the oils’ systemic properties lies in the pregnant patient population who use essential oils thinking that natural is safe.

Many essential oils, such as lavender (L officinalis), exhibit hormonal mimicry with phytoestrogens and can produce emmenagogue (increasing menstrual flow) effects in women. Other oils, such as those of nutmeg (Myristica fragrans) and myrrh (Commiphora myrrha), can have abortifacient effects. These natural essential oils can lead to unintended health risks for mother and baby.¹⁷ With implications this serious, many essential oil companies put pregnancy warnings on most if not all of their products, but pregnant patients may not always note the risk.

Conclusion

Essential oils are not the newest medical fad. They outdate every drug on the market and were used by some of the first physicians in history. It is important to continue research into the antimicrobial effects of essential oils, as they may hold the secret to treatment options with the continued rise of multidrug-resistant organisms. The danger of these oils lies not in their hidden potential but in the belief that natural things are safe. A few animal studies have been performed, but little is known about the full effects of essential oils in humans. Patients need to be educated that these are not panaceas with freedom from side effects and that treatment options backed by the scientific method should be their first choice under the supervision of trained physicians. The Table outlines the uses and side effects of the essential oils discussed here.

What Are Essential Oils?

Essential oils are aromatic volatile oils produced by medicinal plants that give them their distinct flavors and aromas. They are extracted using a variety of different techniques, such as microwave-assisted extraction, headspace extraction, and the most commonly employed hydrodistillation.¹ Different parts of the plant are used for the specific oils; the shoots and leaves of Origanum vulgare are used for oregano oil, whereas the skins of Citrus limonum are used for lemon oil.² Historically, essential oils have been used for cooking, food preservation, perfume, and medicine.^3,4

Historical Uses for Essential Oils

Essential oils and their intact medicinal plants were among the first medicines widely available to the ancient world. The Ancient Greeks used topical and oral oregano as a cure-all for ailments including wounds, sore muscles, and diarrhea. Because of its use as a cure-all medicine, it remains a popular folk remedy in parts of Europe today.³ Lavender also has a long history of being a cure-all plant and oil. Some of the many claims behind this flower include treatment of burns, insect bites, parasites, muscle spasms, nausea, and anxiety/depression.⁵ With an extensive list of historical uses, many essential oils are being researched to determine if their acclaimed qualities have quantifiable properties.

Science Behind the Belief

In vitro experiments with oregano (O vulgare) have demonstrated notable antifungal and antimicrobial effects.⁶ Gas chromatographic analysis of the oil shows much of it is composed of phenolic monoterpenes, such as thymol and carvacrol. They exhibit strong antifungal effects with a slightly stronger effect on the dermatophyte Trichophyton rubrum over other yeast species such as Candida.^7,8 The full effect of the monoterpenes on fungi is not completely understood, but early data show it has a strong affinity for the ergosterol used in the cell-wall synthesis. Other effects demonstrated in in vitro studies include the ability to block drug efflux pumps, biofilm formation, cellular communication among bacteria, and mycotoxin production.⁹

A double-blind, randomized trial by Akhondzadeh et al¹⁰ demonstrated lavender (Lavandula officinalis) to have a mild antidepressant quality but a noticeably more potent effect when combined with imipramine. The effects of the lavender with imipramine were stronger and provided earlier improvement than imipramine alone for treatment of mild to moderate depression. The team concluded that lavender may be an effective adjunct therapy in treating depression.¹⁰

In a study by Mori et al,¹¹ full-thickness circular wounds were made in rats and treated with either lavender oil (L officinalis), nothing, or a control oil. With the lavender oil being at only 1% solution, the wounds treated with lavender oil demonstrated earlier closure than the other 2 groups of wounds, where no major difference was noted. On cellular analysis, it was seen that the lavender had increased the rate of granulation as well as expression of types I and III collagen. The most striking result was the large expression of transforming growth factor β seen in the lavender group compared to the others. The final thoughts on this experiment were that lavender may provide new approaches to wound care in the future.¹¹

Potential Problems With Purity

One major concern raised about essential oils is their purity and the fidelity of their chemical composition. The specific aromatic chemicals in each essential oil are maintained for each species, but the proportions of each change even with the time of year.¹² Gas chromatograph analysis of the same oil distilled with different techniques showed that the proportions of aromatic chemicals varied with technique. However, the major constituents of the oil remained present in large quantities, just at different percentages.¹ Even using the same distillation technique for different time periods can greatly affect the yield and composition of the oil. Although the percentage of each aromatic compound can be affected by distillation times, the antioxidant and antimicrobial effects of the oil remain constant regardless of these variables.² There is clearly a lack in standardization in essential oil production, which may not be an issue for its use in complementary medicine if its properties are maintained regardless.

Safety Concerns and Regulations

With essential oils being a natural cure for everyday ailments, some people are turning first to oils for every cut and bruise. The danger in these natural cures is that essential oils can cause several types of dermatitis and allergic reactions. The development of allergies to essential oils is at an even higher risk, considering people frequently put them on wounds and rashes where the skin barrier is already weakened. Many essential oils fall into the fragrance category in patch tests, negating the widely circulating blogger and online reports that essential oils cannot cause allergies.

Some of the oils, although regarded safe by the US Food and Drug Administration for consumption, can cause dermatitis from simple contact or with sun exposure.¹³ Members of the citrus family are notorious for the phytophotodermatitis reaction, which can leave hyperpigmented scarring after exposure of the oils to sunlight.¹⁴ Most companies that sell essential oils are aware of this reaction and include it in the warning labels.

The legal problem with selling and classifying essential oils is that the US Food and Drug Administration requires products intended for treatment to be labeled as drugs, which hinders their sales on the open market.¹³ It all boils down to intended use, so some companies sell the oils under a food or fragrance classification with vague instructions on how to use said oil for medicinal purposes, which leads to lack of supervision, anecdotal cures, and false health claims. One company claims in their safety guide for topical applications of their oils that “[i]f a rash occurs, this may be a sign of detoxification.”¹⁵ If essential oils had only minimal absorption topically, their safety would be less concerning, but this does not appear to be the case.

Absorption and Systemics

The effects of essential oils on the skin is one aspect of their use to be studied; another is the more systemic effects from absorption through the skin. Most essential oils used in small quantities for fragrance in over-the-counter lotions prove only to be an issue for allergens in sensitive patient groups. However, topical applications of essential oils in their pure concentrated form get absorbed into the skin faster than if used with a carrier oil, emulsion, or solvent.¹⁶ For most minor uses of essential oils, the body can detoxify absorbed chemicals the same way it does when a person eats the plants the oils came from (eg, basil essential oils leaching from the leaves into a tomato sauce). A possible danger of the oils’ systemic properties lies in the pregnant patient population who use essential oils thinking that natural is safe.

Many essential oils, such as lavender (L officinalis), exhibit hormonal mimicry with phytoestrogens and can produce emmenagogue (increasing menstrual flow) effects in women. Other oils, such as those of nutmeg (Myristica fragrans) and myrrh (Commiphora myrrha), can have abortifacient effects. These natural essential oils can lead to unintended health risks for mother and baby.¹⁷ With implications this serious, many essential oil companies put pregnancy warnings on most if not all of their products, but pregnant patients may not always note the risk.

Conclusion

Essential oils are not the newest medical fad. They outdate every drug on the market and were used by some of the first physicians in history. It is important to continue research into the antimicrobial effects of essential oils, as they may hold the secret to treatment options with the continued rise of multidrug-resistant organisms. The danger of these oils lies not in their hidden potential but in the belief that natural things are safe. A few animal studies have been performed, but little is known about the full effects of essential oils in humans. Patients need to be educated that these are not panaceas with freedom from side effects and that treatment options backed by the scientific method should be their first choice under the supervision of trained physicians. The Table outlines the uses and side effects of the essential oils discussed here.