What is the diagnosis and optimal management for a 9‑week pregnant woman with urticaria, angioedema, erythema, and facial edema that began after progesterone suppository use and has persisted for three weeks?

Diagnosis: Autoimmune Progesterone Dermatitis (APD)

This is autoimmune progesterone dermatitis (APD), a rare IgE-mediated hypersensitivity reaction to exogenous progesterone that requires immediate discontinuation of the progesterone suppositories and initiation of high-dose antihistamine therapy. 1, 2, 3

Immediate Management Steps

1. Discontinue Progesterone Suppositories Immediately

• Stop all progesterone supplementation now, as continued exposure will perpetuate the allergic reaction 1, 2, 3
• The 3-week duration of symptoms indicates ongoing exposure is maintaining the reaction 3

2. Assess for Airway Compromise

• Examine for tongue, throat, or laryngeal involvement by asking about dysphagia, voice changes, or breathing difficulty 4
• Monitor for at least 4-6 hours if there is any concern for progression, as angioedema can evolve 4
• If any airway involvement is present, administer intramuscular epinephrine 0.3-0.5 mg immediately 5

3. Initiate Antihistamine Therapy

• Start a second-generation non-sedating H1-antihistamine immediately: cetirizine 10 mg, fexofenadine 180 mg, desloratadine 5 mg, levocetirizine 5 mg, or loratadine 10 mg once daily 4, 5
• Cetirizine has the shortest time to maximum concentration and is preferred when rapid relief is needed 5
• If no response within 2-4 hours, increase the dose up to 4 times the standard dose (this is safe and evidence-based) 4, 5
• Consider adding an H2-antihistamine (ranitidine 50 mg IV or famotidine 20 mg IV) for synergistic effect 4

4. Consider Short-Course Corticosteroids

• Given the severity with angioedema and facial edema, administer oral prednisone 40-60 mg daily for 3-5 days 5
• IV methylprednisolone 125 mg can be used if oral route is not feasible 4
• Limit corticosteroid duration to maximum 10 days to avoid cumulative toxicity 5

5. Symptomatic Relief Measures

• Apply cooling antipruritic lotions such as calamine or 1% menthol in aqueous cream for immediate itch relief 5
• Counsel to avoid aggravating factors: overheating, hot showers, scrubbing, stress, alcohol, and NSAIDs 5

Diagnostic Confirmation

Clinical Diagnosis

• APD is diagnosed by the temporal relationship between progesterone exposure and symptom onset 1, 2, 3
• The presentation of urticaria, angioedema, erythema, and facial edema following progesterone suppository use is pathognomonic 1, 2, 3
• Symptoms typically develop within hours to days of progesterone exposure and persist as long as exposure continues 2, 3

Confirmatory Testing (After Acute Phase Resolves)

• Progesterone skin testing (intradermal or intravaginal challenge) can confirm the diagnosis but should only be performed after symptoms resolve and in a controlled setting 2, 3
• Lymphocyte transformation test (LTT) to medroxyprogesterone can demonstrate enhanced lymphocyte proliferation in vitro 3
• Serum-specific progesterone IgE and IgG antibodies may be detected 6

Obstetric Management Considerations

Pregnancy Support Without Progesterone

• Consult maternal-fetal medicine immediately to determine if progesterone supplementation is absolutely necessary at 9 weeks gestation 7
• If progesterone was prescribed for recurrent pregnancy loss or preterm birth prevention, discuss alternative strategies with the obstetric team 7
• Many pregnancies at 9 weeks can continue successfully without exogenous progesterone supplementation 7

Alternative Approaches if Progesterone is Essential

• If progesterone supplementation is deemed medically necessary, consider progesterone desensitization protocols under specialist supervision, though success is variable 3
• Gonadotropin-releasing hormone agonists (GnRH agonists) have been used in non-pregnant patients but are contraindicated in pregnancy 3, 6
• Close monitoring with serial ultrasounds to assess pregnancy viability without progesterone support 7

Expected Course and Prognosis

Symptom Resolution Timeline

• Symptoms should begin improving within 24-48 hours after discontinuing progesterone and starting antihistamines 2, 3
• Complete resolution typically occurs within 7-10 days after progesterone withdrawal 3
• If symptoms persist beyond 1 week despite treatment, reassess for alternative diagnoses 4, 8

Pregnancy Implications

• APD can paradoxically improve during pregnancy in some cases due to consistently high progesterone levels creating a tolerance state 9
• However, given the severe reaction to exogenous progesterone, close monitoring throughout pregnancy is essential 7
• The condition does not affect fertility or pregnancy outcomes directly 7

Critical Pitfalls to Avoid

Do Not Continue Progesterone

• Continuing progesterone exposure will perpetuate and potentially worsen the allergic reaction 1, 2, 3
• Even small amounts of progesterone can trigger symptoms in sensitized patients 3

Do Not Delay Airway Assessment

• Angioedema can progress rapidly to involve the airway, particularly with ongoing allergen exposure 7, 4
• Facial and lip swelling can herald more serious laryngeal edema 7, 4

Do Not Assume All Progesterone Formulations are Safe

• Cross-reactivity occurs between different progesterone preparations (oral, vaginal, intramuscular) 3
• Synthetic progestins in oral contraceptives can also trigger reactions 3

Do Not Order Extensive Laboratory Workup

• APD is a clinical diagnosis based on temporal relationship to progesterone exposure 1, 2, 3
• Routine laboratory investigations are not indicated unless history suggests alternative diagnoses 5
• Checking C4 levels is only indicated if this becomes a recurrent issue without clear progesterone exposure 4, 8

Follow-Up Plan

Short-Term (1-2 Weeks)

• Reassess in 3-5 days to confirm symptom resolution 5
• Continue antihistamines until complete resolution, then taper over several days 5
• Coordinate with obstetrics regarding pregnancy monitoring and viability assessment 7

Long-Term

• Refer to allergy/immunology for formal evaluation and potential confirmatory testing after pregnancy 8, 5
• Document progesterone allergy prominently in medical records to prevent future exposure 3
• Counsel patient to avoid all progesterone-containing medications and oral contraceptives containing progestins 3
• Discuss contraception options that avoid progestins (copper IUD, barrier methods) for postpartum planning 3