What is the current recommended management for progesterone‑induced (autoimmune) urticaria in a pregnant woman, including clinical presentation, diagnostic work‑up, and treatment options?

Management of Progesterone-Induced Urticaria in Pregnancy

For pregnant women with progesterone-induced urticaria, cetirizine or loratadine (FDA Pregnancy Category B) should be used as first-line therapy, with dose escalation up to 4-fold if needed after 2-4 weeks, while omalizumab 300 mg every 4 weeks serves as second-line therapy for refractory cases. 1

Clinical Presentation and Variants

Progesterone autoimmune dermatitis manifests as cyclic dermatologic symptoms occurring 4 days before to 5 days after menses, typically at the end of the luteal phase when progesterone levels peak. 2 The condition presents with multiple clinical variants:

• Urticaria and angioedema (most common presentation) 2
• Papular and eczematous eruptions 3
• Erythema multiforme 4
• Cyclical eczema 4
• Stomatitis 4
• Anaphylaxis (rare but severe) 4

Paradoxically, pregnancy often results in near-clearance or improvement of urticaria symptoms despite sustained high progesterone levels, though this is not universal. 2

Diagnostic Work-Up

Confirmatory Testing

The diagnosis rests on clinical history combined with provocation testing, as histopathology is non-specific (typically showing subacute spongiotic dermatitis). 3

Intradermal progesterone skin testing is the gold standard diagnostic tool—inject progesterone intradermally and observe for wheal-and-flare reaction within 24-48 hours. 2, 3, 4

Alternative provocation methods include:

• Intravaginal progesterone pessary (practical outpatient option—rash recurs within 12 hours of insertion) 3
• Intramuscular progesterone injection 4
• Oral progesterone challenge 4

Autologous serum skin testing using sera from both estrogenic and luteal phases can elicit positive responses and help rule out other urticarial disorders. 2

First-Line Pharmacologic Management

Antihistamine Therapy

Cetirizine and loratadine are the preferred antihistamines as FDA Pregnancy Category B drugs with no evidence of fetal harm, though controlled human studies are lacking. 1

Chlorphenamine (chlorpheniramine) is often selected by UK clinicians due to its long safety record, despite being a first-generation antihistamine. 1, 5

Dosing algorithm:

• Start with standard doses (cetirizine 10 mg daily or loratadine 10 mg daily) 1
• If inadequate symptom control after 2-4 weeks, escalate up to 4-fold (cetirizine 40 mg daily or loratadine 40 mg daily) 1
• Dose escalation may be initiated earlier when symptoms are intolerable 1

Critical Medication Contraindications

Hydroxyzine is absolutely contraindicated in early pregnancy and should never be used. 1, 5

Diphenhydramine should be avoided as first-line treatment due to its association with cleft palate development. 1

Second-Line Therapy: Omalizumab

For cases refractory to antihistamines, omalizumab 300 mg subcutaneously every 4 weeks is the recommended second-line option. 1

Allow up to 6 months to evaluate response before considering alternatives. 1

Safety Data for Omalizumab in Pregnancy

Real-world evidence strongly supports omalizumab safety:

• A 2024 retrospective study of 29 pregnant patients showed no adverse events, pregnancy complications, or congenital anomalies in newborns exposed to omalizumab before or during pregnancy. 6
• The EXPECT registry demonstrated that first-trimester omalizumab exposure does not increase adverse pregnancy outcomes compared with other pregnant women with moderate-to-severe disease. 1
• Monoclonal antibodies cross the placenta increasingly as pregnancy progresses, making first-trimester exposure theoretically safer than later exposure. 1
• A 2023 international multicenter study (PREG-CU) found that 5.6% of pregnant CU patients used omalizumab with no link between treatment and medical problems at birth. 7

Corticosteroids: Reserve for Severe Exacerbations Only

Limit oral corticosteroids to short 3-day courses for severe acute exacerbations only. 1

Prednisolone is the preferred corticosteroid because approximately 90% is inactivated by the placenta, minimizing fetal exposure. 1, 8, 5

Critical Corticosteroid Warnings

Systemic corticosteroid use in the first trimester is associated with a 3-fold increased risk of isolated cleft lip ± cleft palate, though therapeutic benefit in severe disease may outweigh this risk. 1

Avoid betamethasone and dexamethasone as they cross the placenta more readily than prednisolone. 5

Short tapering courses over 3-4 weeks may be necessary for severe cases, but long-term use should be avoided. 1

Adjunctive Non-Pharmacologic Measures

Identify and minimize aggravating factors including overheating, stress, alcohol, aspirin, NSAIDs, and codeine. 1

Cooling antipruritic lotions (calamine or 1% menthol in aqueous cream) provide symptomatic relief without systemic absorption. 1

Apply emollients regularly to prevent skin dryness, avoid hot baths or showers, and keep nails shortened to minimize scratching. 1, 5

Emergency Management

Intramuscular epinephrine remains life-saving for anaphylaxis or severe laryngeal angioedema even during pregnancy. 1

Dosing: 0.5 mL of 1:1000 (500 µg) for adults and adolescents over 12 years, or fixed-dose epinephrine auto-injectors (300 µg). 1

Prescribe epinephrine auto-injectors for patients at risk of life-threatening attacks, as anaphylaxis is a recognized (though rare) variant of progesterone autoimmune dermatitis. 1, 4

Common Pitfalls to Avoid

Do not assume all pruritic eruptions in pregnancy are benign PUPPP—if symptoms persist beyond 2 weeks postpartum, this strongly favors pemphigoid gestationis or progesterone dermatitis rather than PUPPP. 8

Emergency referrals for chronic urticaria increase the risk of preterm birth, emphasizing the importance of sufficient treatment to keep urticaria under control during pregnancy. 7

Avoid oral decongestants during the first trimester due to conflicting reports of associations with gastroschisis and small intestinal atresia. 1

Do not use prolonged high-potency topical corticosteroids during pregnancy, particularly on large body surface areas. 8, 5

Obstetric Monitoring Considerations

The 2023 PREG-CU study found that preterm birth rate in CU patients was 10.2%, similar to population norms, with no link between urticaria treatments and medical problems at birth. 7

Most patients (60%) used urticaria medication during pregnancy with no increase in adverse outcomes compared to untreated patients (preterm birth: 11.6% vs 8.7%). 7

More than 90% of newborns were healthy at birth regardless of maternal treatment status. 7