Definition and Prevalence

• Pruritus is an unpleasant sensation that causes a strong urge to scratch, negatively impacting psychological and physical well-being.
• Chronic pruritus (CP) is defined as an unpleasant sensation resulting in a need to scratch that lasts more than 6 weeks.
• It is one of the major dermatological complaints during pregnancy.
• Recent studies indicate that 18-40% of pregnant patients experience pruritus.

Associated Conditions

CP can be associated with pregnancy-specific conditions such as:

• Atopic eruption of pregnancy (AEP)
• Polymorphic eruption of pregnancy (PEP)
• Pemphigoid gestationis (PG)
• Intrahepatic cholestasis in pregnancy (ICP)

Pruritus may also arise from:
– Dermatoses coincidentally developing during pregnancy
– Exacerbation of preexisting dermatoses
– Physiological skin changes in pregnancy

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Pregnancy-specific conditions

Atopic Eruption of Pregnancy (AEP)

Definition and Introduction

• In 2005, Ambros-Rudolph et al. introduced AEP as an umbrella term for benign pruritic disorders of pregnancy.
• AEP includes conditions previously diagnosed as eczema of pregnancy, prurigo of pregnancy, and pruritic folliculitis of pregnancy.

Epidemiology

• AEP is the most common dermatosis of pregnancy.
• AEP encompasses:
  • Patients with exacerbation of preexisting atopic dermatitis (approximately 20% of cases).
  • Patients experiencing skin manifestations for the first time during pregnancy.

Risk Factors

• Patients with a family history of atopic dermatitis are at increased risk of developing AEP.
• The disease is often idiopathic, occurring without a known cause.

Types of AEP

• E-type (Eczematous):
• Classical distribution of lesions.
• Eczematous eruption on the face, neck, pre-sternal region, and flexure sides.
• P-type (Prurigo):
• Presence of small, pruritic, erythematous, often grouped papules.
• Predominantly on the extensor surfaces of the extremities and the trunk.

Coexistence and Generalization:

• E and P types often coexist.
• Lesions can generalize.
• Secondary lesions include excoriations from scratching and bacterial or viral superinfection (e.g., eczema herpeticum).

Diagnostic Workup

Medical History and Examination:

• Detailed medical history.
• Comprehensive dermatological examination of the entire skin, including mucosae.

Clinical Presentation:

• Early onset of eczematous/prurigo skin lesions (before the third trimester).
• Involvement of the trunk and limbs.
• Possible atopic family or personal background.

Histopathology:

• Nonspecific and varies with clinical type and stage.
• Skin biopsy is not indicated for diagnosis but may help exclude other causes of pruritus.

Immunofluorescence:

• Direct immunofluorescence (DIF) and indirect immunofluorescence results are negative.

Laboratory Tests:

• Elevated serum immunoglobulin E (IgE) levels in about 30–70% of cases.
• The role of IgE levels as a diagnostic criterion is unclear.

Allergy Tests:

• Prick and patch tests are not recommended during pregnancy.

Treatment

Patient Education:

• Emphasis on sufficient emollient therapy as basic dermatological care.
• Various compounds were studied for their contribution to skin hydration and reduction in pruritus.

Second-line Treatment for Mild and Moderate AEP:

• Topical Glucocorticosteroids:
  • Used to manage mild and moderate AEP.
• Systemic Antihistamines:
  • Recommended alongside topical treatments.
• Narrowband Ultraviolet B (UVB):
  • Recommended for moderate and severe AEP, especially in early pregnancy.
• Second-line Treatment for Severe AEP:
• Systemic Glucocorticosteroids:
  • Short-term use for recalcitrant pruritus.
  • Prednisolone dosage: 0.5–2 mg/kg/day.
• Immunosuppressive Agents:
  • Considered for severe cases unresponsive to phototherapy.
  • Cyclosporine or Azathioprine:
  • Introduced with caution, weighing risks and benefits.
  • Azathioprine may be used off-label if other therapies fail or cyclosporine is contraindicated.

Potential Future Therapy Option:

• Dupilumab:
  • Anti-interleukin-4 receptor (IL-4R)-α antibody.
  • Inhibits IL-4 and IL-13 signaling, affecting various immune cells.
  • Promising safety profile in case reports, but more evidence needed.
  • Recommended to postpone use in pregnancy until more data is available.

Prognosis and Fetal Risks

Reassurance:

• Excellent prognosis for AEP.
• Not associated with adverse fetal outcomes.

Potential Predisposition:

• Children might be predisposed to atopic eczema based on their parents’ atopic background.
• The disease may recur in subsequent pregnancies.

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Polymorphic Eruption of Pregnancy (PEP)

Definition and Epidemiology

• Also known as pruritic urticarial papules and plaques of pregnancy(PUPPP).
• Benign, self-limiting pruritic inflammatory disorder.
• Incidence: 1 in 120 to 1 in 300 pregnancies.
• Typically occurs in the third trimester or immediately postpartum (about 15% of cases).
• Risk factors include:
• First pregnancy (primigravida)
• Excessive maternal weight gain
• Multiple pregnancies

Pathophysiology and Clinical Characteristics

Theories of Pathogenesis

• Skin stretching in the third trimester or over multiple pregnancies may activate dermal nerve endings, leading to pruritus.
• Possible damage to collagen fibers may induce an allergic-type response, contributing to PEP lesions.

Clinical Presentation

• Polymorphic skin lesions: highly pruritic urticarial papules coalescing into plaques.
• Small vesicles (1–2 mm) without bullae.
• Widespread non-urticated erythema, targetoid, and eczematous lesions.
• Generally spares the periumbilical region, this helps to differentiate PUPPP from PG.
• Lesions often start in the abdominal region within striae distensae and spread to thighs, buttocks, and trunk; distal extremity involvement is rare.

Diagnostic Workup

Diagnosis

• Based on clinical presentation.
• No characteristic histological or immunofluorescence findings.
• Prolonged follow-up is recommended to distinguish from pre-bullous pemphigoid gestationis (PG).
• Direct immunofluorescence (DIF) may be performed if there is clinical uncertainty to rule out pre-bullous PG.

Treatment

First-line Treatments

• Emollients
• Antihistamines
• Topical glucocorticosteroids

Severe Cases

• Systemic prednisolone may be considered if the disease is extensive and pruritus does not resolve.

Spontaneous Resolution

• The disease typically resolves within 4–6 weeks, independent of delivery.

Prognosis and Fetal Risks

Prognosis

• PEP is a self-limiting disorder.
• Does not affect the prognosis for the fetus or the pregnant patient.

Recurrence

• Rare, usually occurs only in first pregnancies.

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Pemphigoid Gestationis (PG)

Definition and Epidemiology

• Also known as herpes gestationis.
• Rare self-limited pregnancy-associated bullous autoimmune disease.
• Incidence: Approximately 1 in 2000 to 1 in 60,000 pregnancies.
• Typically occurs in late third trimester but can develop at any time during pregnancy or immediately postpartum.
• Recent reports indicate its occurrence in egg donation pregnancies and rarely in association with trophoblastic tumors.

Pathophysiology and Clinical Characteristics

Pathogenesis

• Similar to bullous pemphigoid with autoantibodies (IgG1 subclass) against bullous pemphigoid antigen 180 (BP180).
• Autoimmunity primarily targets placental proteins, leading to cross-reaction with skin BP180-2 proteins.
• Results in complement activation, eosinophil recruitment, and blister formation at the dermoepidermal junction.

Clinical Presentation

• Initial severe pruritus followed by polymorphic inflammatory skin lesions.
• Erythematous urticarial papules and plaques, often periumbilical, spreading to the abdomen, extremities, and mucosal membranes.
• Progression to tense blisters resembling bullous pemphigoid.

Diagnostic Workup

Diagnosis

• Based on clinical presentation.
• Direct immunofluorescence (DIF) shows linear C3 and/or IgG deposits along the dermo-epidermal junction.
• Histology is nonspecific; biopsy may be performed to exclude other dermatoses.
• Complement-binding tests like ELISA for circulating IgG antibodies against BP180 may be used.

Treatment

First-line Treatments

• High-potency topical glucocorticosteroids and antihistamines to reduce pruritus and prevent blister formation.
• Non-fluorinated topical glucocorticosteroids preferred for less systemic absorption and fewer side effects.

Second-line Treatments

• Short courses of systemic prednisolone if topical treatments are inadequate.
• Other agents like calcineurin inhibitors, intravenous immunoglobulins, dapsone, and azathioprine are considered if refractory to steroids.
• Rituximab before conception may prevent recurrence in subsequent pregnancies.

Prognosis and Fetal Risks

Fetal Prognosis

• Relatively good, but risks include preterm labor and intrauterine growth retardation.
• Risks are likely linked to disease severity rather than treatment.

Association with Other Autoimmune Disorders

• Increased risk of autoimmune disorders in pregnant patients, especially Graves disease.

Recurrence in Subsequent Pregnancies

• Common, with earlier onset and more severe forms reported.

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Intrahepatic Cholestasis in Pregnancy (ICP)

Definition and Epidemiology

• Liver disorder unique to pregnancy.
• Incidence: 0.3–5.6%, with ethnic, geographic, and seasonal variations.
• Striking geographic variation, with higher incidence in certain populations, such as Araucanian Indians (up to 28%).
• Mutations of ABCB4 (MDR3) implicated in biliary secretion of phospholipids may contribute to ICP.
• Associated diseases: gallstones, hepatitis C infection, preeclampsia, and gestational diabetes.
• Characterized by inability to excrete bile salts from the liver, leading to increased serum bile acid concentration and pruritus.
• Typically occurs in the second and third trimesters (>30th week), but earlier onset has been reported sporadically.

Pathophysiology and Clinical Characteristics

Reversible Cholestasis

• Due to impaired excretion of bile salts from the liver.
• Increased serum bile acid concentration leads to pruritus, possibly due to increased availability of brain opiate receptors.
• Negative impact on fetal prognosis.

Etiopathogenetic Factors

• Genetic alterations in hepatobiliary transport proteins.
• Hormonal influences, particularly estrogen levels.
• Environmental factors like seasonal variability and diet.
• Potential role of gut microbiota alterations and long-term therapy with vaginal progesterone preparations.

Clinical Triad

• Severe pruritus, jaundice starting 2–4 weeks after pruritus onset, and elevated bile acids.
• Elevated serum bile acids (>10 μmol/l) and abnormal liver function, mainly serum transaminases.
• Jaundice is not always present, reported in only about 10% of patients.
• Pruritus typically begins on palms and soles, and may become generalized, without primary skin lesions.
• Pruritus may worsen with pregnancy progression, other symptoms include steatorrhea and dark urine.
• Steatorrhea may lead to vitamin K deficiency, requiring careful monitoring of prothrombin time.

Diagnostic Workup

Diagnosis

• Based on clinical presentation and laboratory tests.
• Elevated levels of total serum bile acids are a key indicator.
• Liver function tests may show elevated transaminases.
• Other tests may be performed to rule out associated diseases, such as hepatitis C infection.

Exclusion of Other Conditions

• Exclusion of other cholestatic and hepatic diseases.
• Serum bile acid levels >10 μmol/l.
• Mild elevations in liver transaminases.
• Ultrasound and serologic tests to rule out other potential causes.
• Diagnosis based on characteristic symptoms and increased total serum bile acid levels.

Treatment

First-line Treatments

• Ursodeoxycholic acid (UDCA) is the mainstay of treatment, reducing serum bile acid levels and relieving pruritus.
• Close monitoring of maternal and fetal well-being is essential.
• Delivery may be considered if maternal or fetal complications arise or if the condition worsens despite treatment.

Spontaneous Resolution

• The disease typically resolves within 6 weeks after delivery.

Additional Treatments

• Primary goal: Reduce serum bile acid levels to alleviate symptoms and decrease fetal risks.
• First-line treatment: Ursodeoxycholic acid (UDCA) 15 mg/kg/day or 1 g daily is administered until delivery.
• Consideration of rifampicin synergistic effect in severe cases (>100 µmol/l) if no improvement with UDCA alone.
• Elective delivery after gestation week 37, especially if bile acid concentrations are >100 mmol/l.

Prognosis and Fetal Risks

Prognosis

• Reversible condition with favorable prognosis for both mother and fetus with appropriate management.
• Risks include preterm birth, meconium-stained amniotic fluid, fetal distress, and stillbirth, particularly in severe cases or if untreated.
• Increased vigilance and regular monitoring are necessary to mitigate potential risks to both mother and baby.

Associated Fetal Complications

• Perinatal mortality, stillbirths, low birth weight, preterm birth, and fetal distress during labor.

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General Considerations for Pharmacological Treatment of Chronic Pruritus During Pregnancy

Topical Treatment

• Glucocorticosteroids:
  • First-line treatment for CP with inflammatory skin lesions.
  • Commonly used: Low- or moderate-potency (e.g., methylprednisolone aceponate).
  • Safe: No causal associations with pregnancy outcomes for low- or moderate-potency topical glucocorticosteroids.
  • Caution: Excessive use of potent/very potent steroids (>300 g during pregnancy) may risk low birth weight.
• Calcineurin Inhibitors:
  • Alternative if steroids are contraindicated/refused.
  • Usage: Small areas only, max 5 g/day for 2–3 weeks or as needed.

Pruritus in Pregnancy (Not Specific to Pregnancy)

General Causes of Itching in Pregnancy

• Dry skin (most common cause of generalized itch)
• Renal abnormalities
• Hepatic abnormalities
• Thyroid abnormalities
• Iron deficiency anemia
• Malignancy
• Rheumatic diseases
• Drug reactions
• Diabetes
• Infestations
• Neurologic disorders
• Primary psychiatric disorders
• Systemic infections (e.g., hepatitis, HIV)

Specific Conditions

Atopic Dermatitis

• Chronic inflammatory skin disease
• Associated with skin barrier impairment
• Eczematous lesions and itching
• History of atopy common

Prurigo Nodularis

• Chronic inflammatory skin disease
• Very itchy nodular lesions
• Constant pruritus and scratching
• Unknown pathophysiology

Psoriasis

• Common, long-lasting inflammatory skin disease
• Affects approximately 2% of people
• Red, thick, scaling plaques
• Historically thought not to cause significant itching
• Pruritus commonly affects legs, hands, body, back, and scalp

Notalgia Paresthetica

• Chronic pruritus on the back
• Located lateral to the thoracic spine, interscapular, and paravertebral areas
• Affects women more than men
• Unclear pathogenesis

Other Causes

• Pigmented contact dermatitis
• Pityrosporum folliculitis
• Parapsoriasis
• Neurodermatitis
• Primitive cutaneous amyloidosis

Vulvovaginal Itching

Multiple Etiologies

• Lichen planus
• Atopic and irritant contact dermatitis
• Lichen simplex chronicus
• Lichen sclerosis
• Psoriasis

Vulvovaginal Candidiasis

• Common due to increased estrogen levels
• Usually caused by Candida albicans

Parasitic Infestations

• Pediculosis pubis
• Scabies

Lichenoid Vulvar Diseases

Lichen Sclerosis

• Involves vaginal, perineal, and perianal skin
• Rarely seen during pregnancy

Lichen Planus

• Autoimmune disorder
• Causes pain and intense pruritus (affects approximately 1% of the population)

Lichen Simplex Chronicus

• Eczematoid disorder
• Results in repetitive itch-scratch cycle

Pruritus of Unknown Origin

• Affects 61% of pregnant women

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References

• Pruritus in pregnancy[link]
• Pruritus in Pregnancy[link]
• Pruritus in Pregnancy[link]