A new study published in JAMA Network Open indicates that exposure to tetracycline antibiotics during the first trimester of pregnancy does not elevate the risk of major congenital malformations (MCMs). The findings offer reassurance regarding the use of tetracyclines, particularly doxycycline, when medically necessary during early pregnancy.
The study, a population-based cohort analysis, utilized data from Swedish health and population registries encompassing children born between July 1, 2006, and December 31, 2018. Researchers compared the prevalence of MCMs—such as heart defects, cleft lip, and neural tube defects—in infants exposed to tetracyclines during the first trimester against those who were not.
Tetracyclines are generally avoided from the second trimester onward due to concerns about bone growth inhibition and tooth discoloration in the developing fetus. This study, led by researchers at Sweden's Karolinska Institutet, sought to determine if similar risks existed with first-trimester exposure.
No Elevated Risk of Major Malformations
The research team analyzed data from over 1.2 million children using Sweden's Prescribed Drug Register. They identified 6,341 infants (0.5%) who had been exposed to tetracyclines during the first trimester, with doxycycline being the most common (78.2%). After employing propensity-score matching to control for confounding variables, the researchers compared outcomes between the 6,341 tetracycline-exposed infants and 63,316 unexposed infants.
Among the tetracycline-exposed infants, 252 were diagnosed with any MCM, compared to 2,454 in the unexposed group. The prevalence of any MCM was 39.75 cases per 1,000 among tetracycline-exposed infants and 38.76 cases per 1,000 among unexposed infants.
The study found no statistically significant difference in the risk of any MCM between the two groups (relative risk, 1.03; 95% confidence interval [CI], 0.90 to 1.16). Similarly, the relative risks for specific tetracycline substances were 1.07 (95% CI, 0.93 to 1.23) for doxycycline, 0.83 (95% CI, 0.60 to 1.15) for lymecycline, and 0.78 (95% CI, 0.32 to 1.92) for tetracycline-oxytetracycline.
Secondary outcome analysis revealed no increased risk in 10 of 12 major malformation organ system subgroups and none of 16 individual malformations. Although initial analysis suggested a higher risk for nervous system anomalies (1.92; 95% CI, 0.98 to 3.78) and eye anomalies (1.76; 95% CI, 1.07 to 2.91), these findings did not hold up in a sensitivity analysis extending follow-up to age 3 years.
The authors highlighted the study's large sample size compared to previous research on tetracycline exposure and MCMs. They also emphasized the new evidence provided on previously unreported MCM categories.
Addressing the Gap in Research on Pregnancy and Medication
In an accompanying editorial, Dr. John van den Anker of Children's National Hospital stressed the need for further research on the safety of tetracyclines during pregnancy. He pointed out that pregnant individuals are often excluded from clinical trials, leading to a lack of crucial knowledge for optimal drug use during pregnancy.
Dr. van den Anker called for prioritizing clinical trials and global registries focused on the adverse effects of drug exposure during different trimesters of pregnancy. He emphasized that healthcare practitioners and pregnant patients must carefully weigh the benefits of treatment against potential risks to the fetus until more data becomes available.
