Available online 9 July 2025

What is already known about this topic? Direct challenges are safe and effective in evaluating penicillin allergies in low-risk, non-pregnant patients. Penicillin allergy evaluation in pregnancy is recommended and safety using penicillin skin testing demonstrated. Limited data exists on the safety of direct challenges in pregnancy.

What does this article add to our knowledge? This is the first prospective, randomized controlled trial comparing penicillin skin testing followed by an oral amoxicillin challenge versus a 2-step direct challenge to amoxicillin in low-risk penicillin allergic pregnant patients regardless of trimester.

How does this study impact current management guidelines? This study demonstrated the safety of direct challenges in low-risk penicillin allergic pregnant patients.

The importance of penicillin allergy delabeling in the general population is well known. Its significance is even further highlighted in pregnancy as penicillin based antibiotics are the first line therapy for most infections during or at the time of delivery, particularly group B Streptococcus.

To evaluate the safety of a 2-step direct challenge to amoxicillin without preceding skin testing in pregnant patients with a low-risk penicillin allergy label, regardless of trimester.

We performed a prospective, randomized controlled trial comparing penicillin skin testing (PST) followed by an oral amoxicillin challenge versus a 2-step direct challenge (DC) to amoxicillin without preceding skin testing in pregnant patients regardless of trimester with a low-risk penicillin allergy label.

One hundred forty-four women were including in this study. Seventy-three underwent PST and 70 patients DC. Sixty-eight (93.2%) of women undergoing PST had a negative evaluation for penicillin allergy versus 70 (100%) of women who underwent DC. There were no reactions in either PST or DC groups that required medical treatment, or, notably, administration of epinephrine. DC took significantly less time as compared to PST, with the median time for PST was 75 [IQR 75,80] minutes compared to 65 [IQR 65, 70] minutes for DCs.

For evaluation of penicillin allergy in pregnancy, we demonstrate that a DC is as safe as PST in low-risk pregnant patients.

© 2025 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology