Maternal drug eruption in pregnancy: a differential diagnosis framework

Skin reactions during pregnancy can be alarming for both the patient and the clinician, particularly when a medication is suspected as the trigger. Maternal drug eruptions span a wide clinical spectrum, ranging from mild morbilliform rashes to severe, life-threatening reactions such as Stevens-Johnson syndrome. Distinguishing these from physiologic skin changes and from dermatoses unique to pregnancy is essential for safe maternal-fetal care. A structured differential diagnosis protects the mother from ongoing exposure to a culprit drug while avoiding the unnecessary withdrawal of a needed therapy.

Pregnancy alters immune function, skin physiology, and hepatic metabolism, which in turn modifies how cutaneous drug reactions present. Hormonal shifts can amplify pruritus and pigmentary changes, while expanded plasma volume alters drug pharmacokinetics. In Australia, where prenatal care is delivered through a blend of public hospitals, private obstetricians, and shared-care general practitioners, recognising drug eruptions early has implications for the entire perinatal team.

The clinical challenge is compounded by the relative paucity of safety data for many medications used during gestation. Regulatory bodies such as the Therapeutic Goods Administration provide pregnancy categorisation, yet post-marketing signals often surface only after widespread use. Australian clinicians frequently consult local resources including Therapeutic Guidelines and the Royal Australian and New Zealand College of Obstetricians and Gynaecologists statements when weighing maternal benefit against fetal risk.

Multidisciplinary input is the cornerstone of safe management. Dermatology, allergy, obstetrics, and neonatology each bring a useful lens, particularly when severe reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS) or toxic epidermal necrolysis are considered. The congress described at FAOPS 2020 highlighted how such collaboration shapes perinatal practice across the Asia-Oceania region.

Clinical patterns of drug-induced skin reactions in pregnancy

Drug eruptions classically present within one to three weeks of starting a new agent, although reactions can occur after months of stable exposure. The most common morphology is a morbilliform or maculopapular exanthem, often accompanied by pruritus and low-grade systemic features. Urticarial lesions, fixed drug eruptions, and acneiform rashes are also frequently encountered in obstetric practice.

More severe phenotypes warrant urgent recognition. Stevens-Johnson syndrome and toxic epidermal necrolysis present with painful targetoid lesions, mucosal involvement, and epidermal detachment. DRESS syndrome typically emerges two to eight weeks after drug initiation, with widespread rash, facial oedema, lymphadenopathy, and eosinophilia, alongside potential visceral involvement such as hepatitis or nephritis. Acute generalised exanthematous pustulosis presents abruptly with sterile pustules on an erythematous base, sometimes mimicking pustular psoriasis.

The timing of the eruption in relation to gestational age often narrows the differential. Reactions appearing in the first trimester frequently relate to antiemetics, antibiotics, or supplements, whereas later presentations may involve antihypertensives, tocolytics, or analgesics. Pregnancy itself can modify latency, so a low threshold for suspicion is appropriate when the chronology fits.

Medications most often implicated in pregnancy

Several drug classes recur in case series of maternal cutaneous reactions. Antibiotics, particularly penicillins, cephalosporins, and sulfonamides, are leading culprits, alongside antituberculous agents and antiretroviral therapies where relevant. Anticonvulsants such as lamotrigine, carbamazepine, phenytoin, and levetiracetam carry well-documented cutaneous risks that demand vigilance.

Analgesics and anti-inflammatory drugs, including opioids, non-steroidal anti-inflammatory drugs, and allopurinol, account for a sizeable share of severe reactions. Antihypertensives such as hydralazine and methyldopa, as well as iron and vitamin supplements, can also produce rashes that mimic more ominous disease. Even commonly used agents such as paracetamol and ondansetron are occasionally implicated.

In the Australian context, prescribing patterns follow the Pharmaceutical Benefits Scheme and Therapeutic Guidelines, with first-line agents varying by state. Clinicians in Sydney and Melbourne tertiary centres commonly manage complex referrals from rural and remote regions, where drug exposure histories can be incomplete and traditional or bush medicines may also contribute to the picture. A thorough medication reconciliation, including over-the-counter products and complementary therapies, is therefore essential.

Distinguishing drug eruptions from pregnancy-specific dermatoses

A careful differential separates drug eruptions from the polymorphic dermatoses of pregnancy. Pemphigoid gestationis classically begins on the periumbilical region during the second or third trimester, with tense bullae and intense pruritus, and is associated with anti-BP180 antibodies. Intrahepatic cholestasis of pregnancy presents with severe pruritus, often without primary rash, alongside elevated bile acids and transaminases. Pruritic urticarial papules and plaques of pregnancy (PUPPP) typically arise in the third trimester within striae, sparing the umbilicus.

Atopic eruption of pregnancy is the most common dermatosis of gestation and reflects a flare or new onset of atopic disease. Polymorphous eruption of pregnancy, distinct from PUPPP in some classifications, generally appears in primigravidas with excessive weight gain. Distinguishing these conditions from drug-induced urticaria, fixed eruptions, or early DRESS requires close clinicopathological correlation, sometimes aided by skin biopsy and direct immunofluorescence.

This table summarises the most useful discriminators. Skin biopsy, serology, and liver function tests are often complementary rather than interchangeable.

Diagnostic workup for the pregnant patient

A systematic history anchors the diagnostic process. The clinician should document every medication started within the preceding eight weeks, including prescription, over-the-counter, herbal, and bush medicines. The chronology of rash onset, morphology, progression, mucosal involvement, and systemic symptoms such as fever, lymphadenopathy, or arthralgia guides the differential.

Investigations are tailored to severity. Mild presentations may require only a full blood count, eosinophil count, and liver function tests. Severe presentations warrant urgent biochemistry, including creatinine and electrolytes, viral serology where relevant, and skin biopsy with direct immunofluorescence to exclude autoimmune bullous disease. In suspected DRESS, monitoring of thyroid function and viral reactivation, particularly human herpesvirus 6, is appropriate.

Allergy testing during pregnancy has limitations. Serum specific IgE and tryptase can be informative for immediate reactions, but skin prick and intradermal testing are often deferred until the postpartum period because of the risk of anaphylaxis and the influence of gestational physiology. Photographic documentation and a clearly recorded drug allergy in the Australian My Health Record help prevent recurrent exposure in future pregnancies and across the lifespan.

Treatment considerations across the trimesters

Management begins with prompt withdrawal of the suspected culprit drug, where this can be done safely. Substitution with a structurally unrelated agent is often required, particularly for anticonvulsants, antibiotics, and antihypertensives. Symptomatic care with emollients, oral antihistamines such as loratadine or cetirizine, and topical corticosteroids is generally appropriate for mild reactions.

Moderate to severe reactions call for systemic corticosteroids, typically prednisone, which is considered relatively safe in the second and third trimesters. Severe phenotypes such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS warrant admission to a burns unit or high-dependency setting, with multidisciplinary support. Cyclosporine, intravenous immunoglobulin, and supportive care form the backbone of severe reaction management, with decisions individualised by gestational age and fetal status.

Counselling should address the implications of the drug reaction for future pregnancies and for the neonate. Some agents, such as sulfonamides, carry neonatal risks such as kernicterus if used near term, while others, such as phenobarbital, can produce neonatal withdrawal. Documentation in the discharge summary and communication with the general practitioner and child health nurse support continuity of care across Australian health services.

Implications for the perinatal and neonatal team

Severe maternal drug eruptions can have downstream effects on the newborn. Maternal Stevens-Johnson syndrome or toxic epidermal necrolysis near delivery raises the risk of neonatal involvement through transplacental drug exposure. DRESS and other severe phenotypes may be associated with fetal growth restriction, preterm birth, and the need for special care nursery admission.

Family-centred communication is vital during these frightening experiences. The perinatal team, including midwives, neonatologists, and lactation consultants, should align messaging about feeding, medication safety, and postnatal follow-up. Resources that describe principles of family-centered NICU care can support staff training and parental preparation in Australian tertiary centres such as the Royal Women's Hospital in Melbourne or the Mater Mother's in Brisbane. Coordinated discharge summaries help community teams continue care after families return home.

Reflecting on the broader lessons, clinicians should maintain a high index of suspicion for drug eruptions when rashes arise during pregnancy, even when the suspected agent has been used previously without incident. Thorough documentation, patient education about future avoidance, and shared decision-making with the woman and her family remain essential.

Practical recommendations for the Australian clinician

• Take a comprehensive medication history at every antenatal contact, including over-the-counter, herbal, and bush medicines.
• Document the morphology, distribution, and chronology of every cutaneous reaction with photography where consent is given.
• Record any drug allergy clearly in the My Health Record and the hospital alert system to prevent re-exposure in future pregnancies.
• Collaborate early with dermatology, allergy, and pharmacy colleagues when the diagnosis is uncertain or the reaction is severe.
• Counsel the woman about implications for future pregnancies, breastfeeding, and neonatal monitoring when relevant.
• Escalate suspected Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS to a tertiary centre with burns or high-dependency capability.
• Provide written information and reassurance, recognising the psychological impact of a severe cutaneous reaction during pregnancy.

Continue advancing your team's expertise in perinatal dermatology and high-risk pregnancy care by exploring the scientific programme and abstracts from the FAOPS 2020 congress in Tokyo. The multidisciplinary content, developed with input from leading societies across the Asia-Oceania region, remains a valuable reference for clinicians managing complex maternal and neonatal cases.