A new study published in JAMA Network Open has found that the antibiotic trimethoprim-sulfamethoxazole (TMP-SMX), when used to treat urinary tract infections (UTIs) during early pregnancy, may increase the risk of birth defects. The research highlights the importance of careful antibiotic selection during the first trimester.
UTIs in Pregnancy Common and Often Treated Early
UTIs such as acute cystitis and asymptomatic bacteriuria (ASB) are common in pregnancy. They can lead to serious complications like low birth weight, early delivery, and kidney infections if left untreated. Because of this, doctors typically screen for ASB at the first prenatal visit and start treatment right away.
Two antibiotics—TMP-SMX and nitrofurantoin—have raised concerns in the past due to possible links with birth defects, but earlier studies had limitations. This new study aimed to better understand the safety of these drugs.
How the Study Was Done
Researchers reviewed medical records of over 71,000 pregnant women in the U.S. from 2006 to 2022. All were between 15 and 49 years old and had taken antibiotics for UTIs during their first trimester. The study excluded those with other medical complications or those exposed to drugs known to cause birth defects.
Antibiotics included TMP-SMX, nitrofurantoin, fluoroquinolones (such as ciprofloxacin), and β-lactams (like amoxicillin). β-lactams, which are widely accepted as safe in pregnancy, were used as a comparison group.
Researchers tracked the rate of birth defects in babies using insurance claim data and statistical models to compare risks. They also adjusted for other factors like age, existing health conditions, and medication use.
Key Findings: TMP-SMX Carries Higher Risk
Out of 71,604 pregnancies, nearly 60% involved nitrofurantoin, 31% β-lactams, 5% fluoroquinolones, and 5% TMP-SMX. In total, 1,518 babies were born with congenital malformations.
The study found:
Babies exposed to TMP-SMX had a 35% higher risk of birth defects compared to those exposed to β-lactams.
That equals roughly one extra birth defect for every 145 pregnancies treated with TMP-SMX.
TMP-SMX was especially linked to serious heart defects and facial malformations like cleft lip and palate.
Nitrofurantoin and fluoroquinolones did not show a significantly higher risk than β-lactams.
When examining specific types of defects, TMP-SMX exposure showed:
- More than double the risk for orofacial and respiratory defects.
- A 3.2 times higher risk for cleft lip or palate.
- A 2.1 times higher risk for severe heart defects.
However, the actual difference in the number of cases for these specific malformations was small, and the statistical uncertainty was high.
Robust Findings Across Sensitivity Analyses
To ensure the results were reliable, researchers ran multiple checks:
- They repeated the analysis using different definitions of birth defects.
- They compared only women with symptoms, excluding those with ASB.
- They looked at exposure during key developmental periods in pregnancy.
- They expanded the sample to include over 250,000 pregnancies treated with UTI antibiotics for any reason.
The link between TMP-SMX and increased risk remained steady in all cases. However, for fluoroquinolones, the sample size was too small to draw firm conclusions.
Conclusions and Clinical Implications
This study strongly suggests that TMP-SMX should be avoided during the first trimester when safer alternatives are available. Although TMP-SMX is effective against UTIs, its use in early pregnancy carries a higher chance of causing birth defects compared to β-lactams.
On the other hand, nitrofurantoin appears safe in early pregnancy and should not be restricted based on current evidence.
Doctors should weigh the benefits and risks when prescribing antibiotics during pregnancy and consider using β-lactams or nitrofurantoin instead of TMP-SMX in the first trimester.
Limitations to Keep in Mind
While the study used a large and detailed dataset, it was not a randomized trial. That means other factors—such as underlying health issues—may still affect the results. Also, the study included only live births from women with private insurance, so findings may not apply to all populations.
Still, the evidence supports current medical advice: Use TMP-SMX with caution early in pregnancy and consider safer alternatives when possible.
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