Pruritus in Pregnancy

Etiology

Physiologic, mechanical, endocrine, and immunologic changes during pregnancy, increasing pressure from abdominal growth, and edema may all cause itching. Pruritus in pregnancy may also stem from a variety of other processes, including specific dermatoses of pregnancy, which are the afflictions of the skin that appear during pregnancy and resolve with parturition. This is a heterogeneous group of skin diseases. However, pruritus in pregnancy may also be associated with dermatoses that are not unique to pregnancy or ones associated with pre-pregnancy skin processes. During pregnancy, there is an increase in sex hormones, which affects the production of IgE, mediator release, and mast cells, all of which contribute further to the problem of pruritus in pregnancy.[3]

Pruritus of Pregnancy that IS NOT Specific to Pregnancy

Etiologies that cause itching in pregnancy but are not specifically related to pregnancy include various diseases, such as renal, hepatic, and thyroid abnormalities, iron deficiency anemia, malignancy, rheumatic diseases, drug reactions, diabetes, infestations, neurologic disorders, primary psychiatric disorders, and systemic infection such as hepatitis or HIV.[3] The most common cause of generalized itch is dry skin, which is generalized across the body without apparent causative skin lesions.[4] 

The following conditions are some of the common causes of pruritus during pregnancy but are not specific to pregnancy:

Atopic dermatitis is a chronic inflammatory skin disease associated with skin barrier function impairment. Contact with irritants causes eczematous lesions and itching. Affected patients usually have a history of atopy.[5] 

Prurigo nodularis is another chronic inflammatory skin disease that results in very itchy nodular lesions causing constant pruritus and scratching. The pathophysiology of this skin disease is unknown.[6]

Psoriasis is a fairly common, long-lasting, inflammatory skin disease that produces pruritus. It affects approximately 2% of people. It usually presents with plaques of red, thick, and scaling skin.[7] Historically, psoriasis has not been known to cause significant itching, but this theory has been disproven over the past 10 years. Most patients with psoriasis have some degree of pruritus commonly affecting the legs, hands, body, back, and frequently the scalp.[8]

Notalgia paresthetica is chronic pruritus on the back. It is located lateral to the thoracic spine, in the interscapular and paravertebral area, and medial or inferior to the scapula. It affects women more than men. The pathogenesis is unclear.

Other causes of itching that are not specific to pregnancy include pigmented contact dermatitis, pityrosporum folliculitis, parapsoriasis, neurodermatitis, and primitive cutaneous amyloidosis.[9]

Vulvovaginal itching is not usually specific to pregnancy and has multiple etiologies, including lichen planus, atopic and irritant contact dermatitis, lichen simplex chronicus, lichen sclerosis, and psoriasis. Vulvovaginal candidiasis is a prevalent cause of itching in this area. Typically, Candida albicans is the underlying pathogen responsible for this itching. Due to increased estrogen levels during pregnancy, vulvovaginal candidiasis is quite common. Parasitic vulvar infestations commonly include pediculosis pubis and scabies. These infestations are commonly sexually transmitted.[10]

Lichenoid vulvar diseases are additional dermatoses that affect the vulvar skin. Lichen sclerosis may involve the vaginal, perineal, and perianal skin. It is an inflammatory dermatosis that is rarely seen during pregnancy. Lichen planus is an autoimmune disorder that causes pain and intense pruritus in only about 1% of the population. Lichen simplex chronicus is an eczematoid disorder that commonly affects the vulvar skin, resulting in a repetitive itch-scratch cycle.[10]

A significant percentage (61%) of pregnant women experience itching that cannot be classified and is termed pruritus of unknown origin.[11]

Pruritus of Pregnancy that IS Specific to Pregnancy

There are 5 dermatoses that are specific to pregnancy. These include pemphigoid gestationis, intrahepatic cholestasis of pregnancy, polymorphic eruption of pregnancy, atopic eruption of pregnancy, and pustular psoriasis of pregnancy. In patients with pruritus in pregnancy, approximately 11.8% to 76.4% will have a dermatosis specific to pregnancy.[3] 

Intrahepatic Cholestasis of Pregnancy (ICP) is a cause of itching during pregnancy. Associated characteristics include elevated liver enzymes (transaminases) and serum bile acids (salts). The itching begins in the late second to the early third trimester. However, itching onset as early as 8 weeks of gestation has been described.[12] Other causes of liver abnormalities must be excluded to diagnose ICP. With ICP, pruritus occurs secondary to increased levels of bile acids within the skin and the serum. 

Itching with ICP is usually intermittent at the outset and goes on to become constant. Pruritus begins first in the abdomen and spreads to involve the entire trunk and very specifically occurs on the palms and soles. The itching ranges from mild to severe and bothers the patient most at night.[13] Icterus, if it does manifest, follows pruritus by at least 4 weeks in about 20% of cases.[14] If icterus is present, patients may develop steatorrhea, leading to fat malabsorption. Symptoms persist throughout pregnancy, resolve with childbirth, and may recur with subsequent gestations.[15]

Atopic Eruption of Pregnancy (AEP) is another cause of itching in pregnancy. It is the most frequent dermatosis seen in pregnancy. AEP is diagnosed in 43% to 49% of women with a pruritic rash during pregnancy.[3] It may be associated with a history of atopy in the patient or the patient's family. AEP presents early in pregnancy, frequently as early as the first trimester. It is characterized by discrete papulonodules on the extremities, specifically the extensor surfaces. Lesions are grouped, extremely pruritic, and may be located on the dorsal surfaces of feet and hands. No adverse fetal or maternal outcomes are associated with AEP. The condition may persist until delivery but does not usually recur in the postpartum timeframe.[16]

Polymorphic Eruption of Pregnancy (PEP), also called pruritic urticarial papules and plaques of pregnancy (PUPPP), is also a common cause of itching in pregnancy. Almost 22% of patients with itching in pregnancy are diagnosed with PEP. An extremely itchy rash usually begins in the third trimester or sometimes in the postpartum period and is located within the abdominal striae with occasional spread to the proximal thighs, buttocks, and chest. Sparing of the periumbilical area, face, palms, and soles is usual. It is more common in primiparous patients, with cesarean delivery, and with increased skin distention, as in multiple gestations.[17] PEP is a benign inflammatory disorder with no associated fetal or maternal risks.[18][3] The itching from PEP is likely due in part to stretching of the skin that causes collagen damage, resulting in an allergic response.[11]

Pustular Psoriasis of Pregnancy is a very rare variant of pustular psoriasis, which typically presents in the third trimester of pregnancy in women who frequently have no history of psoriasis. The pustules occur on red patches of skin located in the groin, axillae, and inframammary folds. The pustules become large plaques that spread to the trunk and bilateral extremities, sparing the palms, head, and soles. Mucous membranes, such as oral and esophageal, may be involved. The associated itching is usually mild, but patients may have other symptoms, specifically fever, chills, and diarrhea. Lymphadenopathy and malaise may also be present. Elevated white blood cell count, and sedimentation rate, and low calcium, phosphorus, and vitamin D from hyperparathyroidism may be seen.[3]

Pemphigoid Gestationis (PG) is a rare disorder of pregnancy that causes pruritus from an underlying autoimmune process. Pruritis usually begins in the second or third trimester. Lesions most commonly involve the extremities but may affect the whole body, with the sparing of mucous membranes. PG commonly improves as pregnancy progresses, but it may flare around the delivery time in 75% of affected patients. A small percentage of newborns will develop skin lesions that resolve spontaneously within several days to weeks. Pregnancy and fetal prognoses are unaffected, and the skin condition resolves postpartum. However, it may recur in future pregnancies.[3]

Epidemiology

Pruritus is reported by 23% to 38% of women during pregnancy, with 2% having severe itching. It is a burdensome symptom that may be the first sign of a pregnancy-specific disease.[19] Approximately 11.8% to 76.4% will have a dermatosis specific to pregnancy as an etiology of their pruritus.[3][11] On average, itching in pregnancy starts at or just after 27 weeks of gestation. The most common sites for pruritus during pregnancy, in decreasing order, are the abdomen, chest, hands, feet, and lower legs. Itching of the anogenital area is rarely reported in pregnancy. Itching occurs most frequently in the evenings, with half of patients reporting trouble sleeping. Sweat, heat, and dry air frequently exacerbate the itching. The true incidence of pruritus in pregnancy is unknown and is likely higher than previously reported.[11][3]

Pathophysiology

Water loss through the epidermis from skin barrier-related damage leads to a loss of flexibility of the stratum corneum and resulting pruritus.[1] Itching is related to the underlying pathophysiology of each specific disease process, as noted above.

Histopathology

Pruritus in pregnancy is likely caused to some extent by stretching of the skin, which causes the firing of dermal nerve endings.[11]

Polymorphic eruption of pregnancy (PEP) is characterized by nonspecific skin changes. These changes range from mild spongiosis to perivascular lymphocytic infiltration mixed with neutrophils or eosinophils. Dermal edema is evident. Immunofluorescence, both direct and indirect, are negative.[18] The histopathology varies by the stage of lesions, with nonspecific findings most often. 

Pemphigoid gestationis (PG) is characterized initially by dermal edema and perivascular infiltration of lymphocytes, histiocytes, and eosinophils. A subepidermal split and bullae follow. Linear deposits of complement 3 are visualized along the basement membrane of the skin adjacent to the lesions in all patients.[18]  

Intrahepatic cholestasis of pregnancy (ICP) is not typically associated with a rash or visible skin changes. Itching is commonly located on the palms of the hands and soles of the feet. The exact mechanism by which bile salts (or acids) induce pruritus is not well understood. Due to their detergent properties, bile salts can lead to the release of histamine and proteolytic enzymes through the solubilization of lipid cellular membranes. The release of histamine and other enzymes can activate free nerve endings, leading to pruritus.[20] The levels of bile acids rise secondary to hormonal and genetic factors. With levels increasing during pregnancy, hormones such as estrogen and progesterone have a cholestatic effect and reduce the hepatic excretory function.[13] 

Psoriasis results from the production of proinflammatory cytokines from the activation of T lymphocytes, resulting in inflammation and proliferation of the skin[7]. Genital psoriasis may accompany psoriasis on other areas of the skin, but 2% to 5% of cases may be localized to the vulvar skin.[10] During pregnancy, psoriasis may improve in some patients and worsen in others. 

The vulvar skin is very prone to pruritus because the skin's barrier function in this area is weaker than in other areas of the body. Transepidermal water loss is higher in the area, and the skin reacts more to irritants. An underlying infectious, neoplastic, or inflammatory process may cause vulvovaginal itching.[10]

History and Physical

Itching is an irritating sensation that evokes the impulse to scratch. Evaluation of pregnant patients with itching includes a detailed history and physical examination, explicitly looking for primary skin lesions associated with the itching. The location, timing, and duration of pruritus and any remedies tried should be elicited to help diagnose the cause and provide efficacious treatment. Medication use, pruritus in other family members, and travel history should also be part of the detailed history.[3]  Various methods for assessing itching are available for use. Following the European Guideline on Chronic Pruritus may help discern the etiology of itching. Laboratory evaluation may be beneficial depending on the differential diagnosis in consideration.[11]

Physical examination does not yield evidence of primary lesions in ICP. The diagnosis of ICP is rejected if any primary lesions are present.[21] Excoriations and scratch marks secondary to itching are the only typical examination findings.

Vulvovaginal itching caused by a yeast infection is characterized by itching, burning, and sometimes dysuria and dyspareunia. Vaginal discharge, vulvar erythema, pustules, or erosions may be present on physical examination. Lichen simplex chronicus is described as varying degrees of erythema and scaling of the vulvar skin with lichenified plaques and excoriations. Burrows in the vulvar area may be seen with scabies, and adult lice and their eggs may be visible with pediculosis pubis.[10]

Evaluation

Pruritus in pregnancy may or may not be associated with primary skin lesions. When primary skin lesions are present, this usually indicates a dermatologic disorder. Secondary lesions, including excoriations, lichenification, and hyperpigmentation, are reactive skin changes resulting from scratching and chronic rubbing. Determining the location of the itching and/or lesions is essential. The location may be generalized or localized. Timing of onset, aggravating factors, alleviating factors, and lesion morphology are important in evaluating pruritus in pregnancy.[3] Initial testing may include liver function tests, complete blood count, basic metabolic panel, thyroid-stimulating, hormone, and bile acids. Further workup should be directed based on initial findings but may include protein electrophoresis, HIV testing, stool for ova and parasites, and hepatitis testing.

Puritis without skin lesions may suggest cholestasis of pregnancy or psychogenic, systemic, or neurologic etiologies. Additional etiologies include nostalgia paresthetica, postherpetic neuralgia, cerebral infarct, vulvodynia, and brachioradialis pruritus.[3]

Treatment / Management

The goal of treatment should be focused on the alleviation of symptoms and the prevention of potential adverse outcomes in the fetus. Mild symptoms may be treated with reassurance, education, psychological strategies, antipruritic topical preparations, and weak steroidal ointments.[22][1] Patients should be advised to avoid anxiety and irritating clothing.[23] (B3)

Skin barrier-related itching is treated initially with topical therapies, including emollients (water and lipids), corticosteroid creams and ointments, immunomodulators, capsaicin, local anesthetics, and oral and topical antihistamines. The topical therapies, in the form of creams, lotions, or ointments, target areas of the skin in close proximity to the stratum corneum. A combination of topical and systemic therapies may be needed to stop the itch-scratch cycle. Therapy must then be tailored to the individual patient and underlying cause. A high frequency of recommended use for topical agents and unpleasant side effects are common reasons for noncompliance with use, resulting in the failure of a specific treatment regimen.[1](B3)

Topical steroids are generally considered safe in pregnancy, but high-potency steroids may cause fetal growth restriction, skin thinning, and increased striae. Therefore, mild- to moderate-potency steroids are recommended topically as initial treatment. If high-potency steroids are needed to control pruritus, limiting the duration and avoiding areas of thin skin (specifically eyelids, axilla, genitals, and skin flexures) are advised.[3] 

Topical azoles are minimally absorbed and may safely treat vaginal or topical yeast and fungal infections during pregnancy. Studies have shown no association between these topical and vaginal antifungal creams, such as clotrimazole and miconazole, and fetal malformations or increased rates of abortion. The safest oral antifungal agent to use in pregnancy is terbinafine, but low-dose fluconazole at 150 mg or less may be safely used. Oral azoles, like ketoconazole and griseofulvin, have been linked to potential complications such as spontaneous abortion, fetal eye defects, congenital heart anomalies, and musculoskeletal malformations. Therefore, topical antifungal agents are the preferred treatment in pregnancy.[19]

The data on the safety of medications used to treat pruritus in pregnancy is somewhat limited. First-generation antihistamines like diphenhydramine, chlorpheniramine, pheniramine, or tripelennamine are safe during pregnancy and may be used to treat pruritus.[23] Other drugs that may be used, especially for refractory pruritus, include cholestyramine, S-adenosyl-D-methionine, oral corticosteroids, nonerythemogenic UVB radiation, and phenobarbital. These drugs are used more in the treatment of ICP.

Polymorphic Eruption of Pregnancy (PEP): Itching from PEP may be treated with low- to mid-potency steroids applied topically. Hydrocortisone 2.5%, and desonide 0.05%, are examples of low-potency topical steroids, while triamcinolone 0.1%, mometasone 0.1%, or fluocinolone 0.025% are examples of mid-potency steroids that may be used. Emollients and antihistamines, such as chlorpheniramine, loratadine, and cetirizine, may also be used.[17] A short course of systemic corticosteroids or ultraviolet phototherapy may treat intractable itching.[3]

Atopic Eruption of Pregnancy (AEP): Itching from AEP may be treated with antihistamines, mild soaps, emollients, and low- to mid-potency topical steroids. If these therapies do not relieve the xerosis and itching, phototherapy or oral corticosteroids may be necessary.[3][18]

Pemphigoid Gestationis (PG): Treatment for itching from PG begins with upper-middle strength topical steroids. High-potency corticosteroids applied topically may be used initially for blister suppression. If this initial therapy is not adequate, systemic corticosteroids may be recommended, starting with 0.5 mg/kg daily and tapering to a lower daily dose. However, severe itching may require 1 mg/kg to 2 mg/kg per day. Tapering steroids should only start after new blister formation has stopped for at least 2 weeks. Oral antihistamines may be added. Case reports have also used rituximab (only in postpartum women), intravenous immunoglobulin, azathioprine, dapsone, and cyclosporine.[3][18]

Intrahepatic Cholestasis of Pregnancy (ICP): Itching from ICP is initially treated with oral ursodeoxycholic acid 10 mg/kg to 15 mg/kg daily. This treatment not only helps to alleviate pruritus but also lowers serum liver transaminase levels. Ursodeoxycholic acid works by increasing hepatobiliary secretion. Doses up to 20 mg/kg per day are safe in pregnancy. In addition, ursodeoxycholic acid treatment has been shown to reduce stillbirth and preterm birth rates, an additional clinical benefit of treatment. More recently, rifampicin 150 mg to 600 mg daily has been used safely and effectively in the third trimester as a treatment for ICP.[24] (B3)

There are increased risks of adverse fetal and neonatal outcomes with ICP, including increased risk of preterm birth, meconium-stained amniotic fluid, neonatal depression, respiratory distress syndrome, and stillbirth.[25] In contrast, maternal risks are small.[26] To attempt to decrease the risk of adverse events, the American College of Obstetricians and Gynecologists (ACOG) recommends antenatal surveillance with fetal non-stress tests after viability and beginning at the time of diagnosis of cholestasis and continuing once or twice weekly until delivery[27]. The serum's total bile acid levels determine the recommended delivery timing. For a total bile acid level <100 micromol/L, delivery is recommended between 36 0/7 to 39 0/7 weeks of gestation. For a total bile acid level ≥100 micromol/L, delivery is recommended at 36 0/7. If the patient is diagnosed with cholestasis at a gestational age later than the recommended gestation for delivery, delivery is recommended at the time of diagnosis.[26][28](B3)

Differential Diagnosis

Primary Skin Lesions Present

• Polymorphic eruption of pregnancy (PEP) - This benign inflammatory disorder of the skin in pregnancy was previously called pruritic urticarial papules and plaques of pregnancy (PUPPP). It is one of the common dermatoses of pregnancy, occurring in 1 in 200 to 250 pregnant women. This condition is more common in first pregnancies, multiple pregnancies, and obese patients. It typically presents during the third trimester with intensely itchy urticarial papules and plaques that are present in the striae on the abdomen with sparing of the palms, soles, umbilicus, and face. Differential diagnosis of PEP includes large cell lymphoma, scabies, viral skin rash, and impetigo herpetiformis.[17]
• Atopic eruption of pregnancy (AEP) - This condition includes prurigo of pregnancy, pruritic folliculitis of pregnancy, and eczema of pregnancy, which are now all grouped together. It is the most common dermatosis seen in pregnancy.
• Pemphigoid gestationis (PG) - previously called herpes gestationis
• Pustular psoriasis of pregnancy (PPP)                                                                                                                                                                                                                                                            

Primary Skin Lesions Not Present

• Psychogenic disorders
• Systemic diseases
• Neurologic conditions
• Renal abnormalities
• Liver abnormalities
• Endocrine disorders (thyroid and diabetes)
• Iron deficiency anemia
• Malignancies
• Rheumatic disease
• Drug reactions
• Systemic infections, such as HIV
• Dry skin or xerosis
• Intrahepatic cholestasis of pregnancy

Prognosis

Patients should be counseled regarding the temporary nature of the disease and the expected, usually prompt, resolution of their symptoms following delivery, particularly in cases of itching from pregnancy-specific dermatoses. In dermatoses not specific to pregnancy, the prognosis varies based on the etiology of the pruritus.

With ICP, the maternal and fetal prognosis is excellent, with increased fetal surveillance, treatment with medications to reduce bile acids, and early delivery per the above recommendations. 

Complications

Complications of pruritus in pregnancy vary for the mother and the fetus depending upon etiology. With ICP, complications to the mother may include malabsorption and/or postpartum bleeding caused by reduced vitamin K levels due to liver abnormalities.[12] One study found an increased incidence of gallbladder disease, including cholelithiasis, in affected patients.[29] 

With ICP, complications to the fetus include premature birth, intrauterine asphyxia, meconium-stained amniotic fluid, and low birth weight.[30] Bile acid levels ≥40 micromol/L and particularly >100 micromol/L are statistically significant for increased adverse events in the fetus.[31] Fetal complications are believed to arise from placental anoxia and the possible deleterious effects of high bile acid levels on the fetal heart. However, an overall limited understanding of the pathophysiology and mechanisms involved in the adverse outcomes associated with ICP remains.[32]