Larger Study Supports Safety of Tetracyclines During Early Pregnancy

The link between first trimester tetracycline exposure and major congenital malformations (MCMs) was not supported by a large cohort study based on Sweden’s national registers.

Incidence of any MCM diagnosed in the first year of life reached 39.75 cases per 1,000 exposed infants versus a similar 38.76 cases per 1,000 unexposed infants (RR 1.03, 95% CI 0.90-1.16), according to a group led by Aya Olivia Nakitanda, MD, PhD, of Karolinska Institutet in Stockholm.

Results in 10 out of 12 malformation subgroups supported the safety of tetracyclines. The two exceptions were possible excess 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, but these findings did not hold up in a sensitivity analysis with MCM follow-up extended to age 3 years.

Furthermore, researchers could not link first trimester tetracycline exposure to any of 16 individual malformations, they reported in JAMA Network Open.

“Although this study counters prior safety signals and provides new evidence on previously unreported MCM categories, statistical precision remained limited for several MCM subgroups and individual MCMs,” Nakitanda and colleagues wrote.

Tetracycline antibiotics are widely used for a variety of common bacterial infections.

Pregnant women are advised to avoid tetracyclines after 4 months of pregnancy except under special circumstances, due to potential associations with developmental malformations in the fetus, lifelong caramel discoloration of the teeth, and, more rarely, lethal drug-induced liver toxicity in pregnant individuals. Prior observational work has also suggested an increased risk of heart defects associated with tetracyclines.

The present Swedish cohort study was based on maternal prescription fills linked to babies born from 2006 to 2018. The cohort counted nearly 70,000 infants (51.5% boys) after tetracycline-exposed infants — 6,340 who had been exposed to doxycycline, lymecycline, or tetracycline-oxytetracycline — were matched 1:10 to unexposed controls on propensity score weighting.

Nakitanda’s group warned that they could not exclude potential selection bias from their study as pregnancies that resulted in spontaneous abortion, termination, or stillbirth were not part of the cohort. Exposure misclassification was another potential caveat due to the absence of data on inpatient antibiotic use or actual intake of antibiotics or the timing of use.

Thus, despite the study being considerably larger than earlier reports probing the safety of tetracyclines during pregnancy, the jury is still out pending more definitive evidence — particularly with regard to doxycycline, the most frequently used tetracycline during pregnancy, according to John van den Anker, MD, PhD, of Children’s National Hospital in Washington, D.C.

“This lack of necessary knowledge for optimal use of doxycycline or any of the other tetracyclines during pregnancy all boils down to the fact that pregnant persons still need to be viewed as therapeutic orphans. Pregnant individuals (and those of child-bearing potential) have historically been excluded from clinical trials because of the well-intentioned attempt to protect the vulnerable fetus,” van den Anker wrote in an accompanying editorial.

“Participation in clinical (drug) trials, global registries to document possible adverse effects of exposure to drugs during the different trimesters of pregnancy and during lactation, and an active surveillance system to detect and document possible adverse effects are only a few of the steps necessary to adopt these therapeutic orphans,” he urged. “Priority needs to be given to clinical trials and global registries focusing on anti-infective drug use during pregnancy.”

For their study, Nakitanda and colleagues relied on a database covering all prescriptions filled in Sweden. They defined exposure in the first trimester as at least one tetracycline prescription filled by the mother between the first day of the last menstrual period and 97 days of gestation.

They showed that 0.5% were exposed to tetracyclines during the first trimester.

Before propensity matching, mothers of tetracycline-exposed infants were more often in the youngest and oldest age strata and tended to be Swedish-born and had lower levels of education, more diagnosed substance use disorders, and more smoking during early pregnancy.

The adjusted analysis showed no significant increase in ear, neck, or face anomalies; congenital heart defects; respiratory anomalies; orofacial clefts; genital abnormalities; limb abnormalities; and other malformation subgroups associated with tetracyclines.