First-trimester antibiotic treatments for urinary tract infections and risk of congenital malformations

Monday, August 26, 2024

1:30 PM – 1:45 PM CEST

Location: Room XV

Presenting Author(s)

Yanmin Zhu, MS, PhD

Instructor in Medicine
Brigham and Women's Hospital and Harvard Medical School
Boston, United States

Co-Author(s)

KF

Kelly Fung, MS

Research Specialist
Brigham and Women's Hospital and Harvard Medical School, United States
BB

Brian T. Bateman, MD, MSc

Stanford University
Palo Alto, United States
Sonia Hernandez-Diaz, MD, DrPH

Professor of Epidemiology
Harvard T.H. Chan School of Public Health
Boston, United States
CL

Chih-Wan Grace Lin, PhD

Postdoctoral Research Fellow
Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, United States
KG

Kathryn J. Gray, MD PhD

Associate Professor
University of Washington
Seattle, United States
MP

Malavika Prabhu

Massachusetts General Hospital, United States
AC

Andrea Ciaranello

Massachusetts General Hospital, United States
LR

Laura Riley

Weill Cornell Medicine, United States
HM

Helen Mogun

Brigham and Women's Hospital, United States
Elyse C. DiCesare, BA

Research Assistant
Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital and Harvard Medical School, United States
Gauri Bhatkhande, MPH

Brigham and Women's Hospital, United States
Krista F. Huybrechts, PhD, MS

Associate Professor of Medicine
Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School
Boston, United States

Background: Urinary tract infections (UTI) affect approximately 8% of pregnancies and cause adverse pregnancy outcomes if left untreated. Amoxicillin and cephalexin are considered safe in pregnancy. While nitrofurantoin and trimethoprim-sulfamethoxazole (TMP-SMX) are effective treatments for UTI and commonly used in pregnancy, potential signals for congenital malformations (e.g., cardiac malformations, oral clefts) have been reported. Fosfomycin is increasingly being used to treat UTI in pregnancy despite limited safety data.

Objectives: To evaluate the risk of congenital malformations following the use of nitrofurantoin, TMP-SMX, and fosfomycin during the first trimester of pregnancy.

Methods: We conducted a cohort study of pregnant women with live births using nationwide US Medicaid (2000-2018) and MarketScan (2003-2021) data. The 3 exposure groups included women with ≥1 filled prescription for nitrofurantoin, TMP-SMX, or fosfomycin during the first trimester. Each exposure group was compared to 2 reference groups: women with ≥1 amoxicillin or cephalexin prescription fill during the first trimester. Patients in the TMP-SMX, amoxicillin, and cephalexin groups were required to have ≥1 UTI related diagnosis/procedure code within 6 days of the fill date because these antibiotics are commonly used to treat other infections. We estimated the relative risks (RR) with 95% confidence intervals (CI) of major congenital malformation (MCM) overall and of organ system specific malformations. Propensity score overlap weights were used to control for potential confounders, and estimates from each database were combined using meta-analysis.

Results: We identified 179,805 (4.1%) eligible pregnancies exposed to nitrofurantoin, 13,809 (0.3%) exposed to TMP-SMX, 261 (0.01%) exposed to fosfomycin, 44,064 (1.0%) exposed to cephalexin, and 37,863 (0.9%) exposed to amoxicillin. The pooled adjusted RR of MCM was 1.04 (95% CI, 0.98-1.11) for nitrofurantoin vs. amoxicillin and 0.97 (0.92-1.03) vs. cephalexin; 1.05 (0.94-1.16) for TMP-SMX vs. amoxicillin and 0.98 (0.88-1.09) vs. cephalexin. No increased risks for organ specific malformations were found for nitrofurantoin and TMP-SMX based on the pooled adjusted RR, though the CIs were wide for certain rare malformations. The pooled crude RR of MCM was 0.72 (0.33-1.60) for fosfomycin vs. amoxicillin and 0.63 (0.28-1.38) vs. cephalexin. There were too few fosfomycin-exposed pregnancies to evaluate the adjusted RR of MCM and risk of specific malformations.

Conclusions: Nitrofurantoin, TMP-SMX, and fosfomycin use in the first trimester was not associated with congenital malformations in the offspring when compared with cephalexin or amoxicillin.