2-Step Direct Amoxicillin Challenge Found Safe in Low-Risk Pregnant Patients

A 2-step direct challenge is just as safe as penicillin skin testing in low-risk pregnant patients, a recent study found.1

Previous research has already demonstrated the safety and efficacy of direct challenges for evaluating penicillin allergies. A clinical trial showed that the PEN-FAST clinically validated decision rule provides a point-of-care risk assessment for individuals with reported penicillin allergies.2 A score < 3 reliably predicts low-risk allergies, with a negative predictive value of 96.3% (95% confidence interval [CI], 94.1% - 97.8%).

“Compared with skin testing, a direct oral penicillin challenge is less resource and time intensive, is less expensive, and has the potential to be performed outside of the specialist allergy setting, providing a scalable approach to address low-risk, unverified penicillin allergy in diverse treatment settings internationally,” wrote investigators of this earlier study, led by Maria Copaescu, MD, from McGill University Health.

However, the efficacy of direct challenges to assess penicillin allergies was not evaluated in low-risk, pregnant individuals.1 To fill this gap, investigators, led by Sara Patrawala, MD, a clinical allergist/immunologist from Rochester Regional Health in New York, aimed to assess the safety of 2-step direct challenge to amoxicillin without prior skin testing in pregnant patients with a low-risk penicillin allergy label.

Evaluating penicillin allergy is especially important during pregnancy. An estimated 13% to 15% of pregnant women have a penicillin allergy documented in their medical records; however, 98% to 99% of those tested as adults are no longer truly allergic.3

Penicillin-based medications are first-line treatments for many infections, including mastitis, endometritis or group B Streptococcus infections.1 These medications are also more effective when it comes to C-sections. Alternative medications lead to delayed recovery and unnecessary adverse events.

The team conducted a prospective, randomized controlled trial comparing a 2-step direct challenge to amoxicillin without previous skin testing versus penicillin skin testing followed by an oral amoxicillin challenge. The sample included 144 women at any trimester of their pregnancy and who had a low-risk penicillin allergy label.

In the analysis, 73 women underwent penicillin skin testing and 70 underwent a 2-step direct challenge. A negative evaluation for penicillin allergy occurred in 93.2% of women undergoing penicillin skin testing and 100% undergoing a 2-step direct challenge. No participant undergoing either evaluation experienced reactions requiring medical treatment.

A 2-step direct challenge took significantly less time than penicillin skin testing (75 minutes vs 65 minutes).

“This study demonstrated the safety of direct challenges in low-risk penicillin allergic pregnant patients,” investigators wrote.

References

1. Patrawala S, Mustafa SS, Kraude R, Ramsey A. A Randomized Trial Comparing Direct Challenges to Penicillin Skin Testing for Outpatient Low-Risk Penicillin Allergy Evaluations in Pregnancy. J Allergy Clin Immunol Pract. Published online July 9, 2025. doi:10.1016/j.jaip.2025.07.003

2. Smith, T. Direct Oral Penicillin Challenge Effective in Assessment of Low-Risk Allergy. HCPLive. September 5, 2023. https://www.hcplive.com/view/direct-oral-penicillin-challenge-effective-assessment-of-low-risk-allergy. Accessed July 18, 2025.

3. Penicillin allergy test recommended for pregnant women. VUMC News. February 16, 2023. https://news.vumc.org/2023/02/16/penicillin-allergy-test-recommended-for-pregnant-women/. Accessed July 18, 2025.