A large cohort study from Sweden's national registers found no significant link between first-trimester tetracycline exposure and major congenital malformations (MCMs). The study, led by Aya Olivia Nakitanda, MD, PhD, of Karolinska Institutet in Stockholm, examined nearly 70,000 infants born between 2006 and 2018.
The incidence of any MCM diagnosed within the first year of life was 39.75 per 1,000 exposed infants, compared to 38.76 per 1,000 unexposed infants (RR 1.03, 95% CI 0.90-1.16). These findings, published in JAMA Network Open, suggest that tetracycline use during early pregnancy may not pose a significant risk of major birth defects.
Detailed Findings on Malformation Subgroups
Out of 12 malformation subgroups analyzed, 10 supported the safety of tetracyclines. However, there were possible excesses in nervous system anomalies (RR 1.92, 95% CI 0.98-3.78) and eye anomalies (RR 1.76, 95% CI 1.07-2.91) associated with tetracycline exposure. These findings did not hold up in a sensitivity analysis extending MCM follow-up to age 3 years. The researchers found no link between first-trimester tetracycline exposure and any of 16 individual malformations.
Context and Current Recommendations
Tetracycline antibiotics are commonly prescribed for various bacterial infections. Current guidelines advise pregnant women to avoid tetracyclines after 4 months of pregnancy due to potential fetal developmental issues, including tooth discoloration and, rarely, liver toxicity. Previous studies have also suggested a possible increased risk of heart defects.
Study Design and Limitations
The Swedish cohort study linked maternal prescription fills to infant birth records. The study included 6,340 infants exposed to doxycycline, lymecycline, or tetracycline-oxytetracycline, matched 1:10 with unexposed controls using propensity score weighting. Exposure was defined as at least one tetracycline prescription filled between the first day of the last menstrual period and 97 days of gestation; 0.5% of the cohort was exposed to tetracyclines during the first trimester.
The researchers acknowledged potential selection bias due to the exclusion of pregnancies ending in spontaneous abortion, termination, or stillbirth. Misclassification of exposure was also a concern, given the lack of data on inpatient antibiotic use, actual antibiotic intake, and timing of use.
Expert Commentary
John van den Anker, MD, PhD, of Children's National Hospital in Washington, D.C., noted the limitations in knowledge regarding doxycycline use during pregnancy. In an accompanying editorial, he emphasized the need for clinical trials and global registries to document potential adverse drug effects during pregnancy. "Priority needs to be given to clinical trials and global registries focusing on anti-infective drug use during pregnancy," van den Anker urged.
Nakitanda and colleagues concluded that while their study provides new evidence on MCM categories and counters prior safety signals, statistical precision remained limited for several MCM subgroups and individual MCMs. More definitive evidence is needed, especially concerning doxycycline, the most frequently used tetracycline during pregnancy.
