Exposure to tetracycline antibiotics during the first trimester of pregnancy is not tied to increased risks of major congenital malformations (MCMs), researchers reported yesterday in JAMA Network Open.
The findings are from a population-based cohort study that used data from Swedish health and population registries on children born from July 1, 2006, to December 31, 2018. The study compared MCMs—such as heart defects, cleft lip, cleft palate, and neural tube defects—among children who were exposed to tetracyclines during the first trimester and those who weren't.
Antibiotics are among the most common medications prescribed during pregnancy, but tetracyclines are not recommended from the second trimester onward because they pass through the placenta and have been implicated in inhibition of bone growth and lifelong discoloration of teeth. A team led by researchers from Sweden's Karolinska Institutet wanted to see if those concerns might also pertain to tetracycline use during the first trimester.
"Safety information is crucial to guide prescribing and communicate risks in clinical situations that necessitate tetracycline use during pregnancy," the study authors wrote. "We aimed to investigate the association between first trimester tetracycline exposure and risk of major congenital malformations (MCMs)."
No increase in MCM risk in infants
For the study, the researchers analyzed data on more than 1.2 million children from Sweden's Prescribed Drug Register, which contains records of all prescriptions filled at pharmacies in Sweden. They found that 6,341 infants (0.5%) were exposed to tetracyclines during the first trimester, primarily doxycycline (78.2%). Using propensity-score matching to account for confounding, the researchers compared outcomes among the 6,341 tetracycline-exposed infants and 63,316 unexposed infants.
A total of 252 infants exposed to tetracycline during the first trimester received a diagnosis of any MCM, compared with 2,454 unexposed infants. 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 risk of any MCM did not differ between the groups (relative risk, 1.03; 95% confidence interval [CI], 0.90 to 1.16). The RRs 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.
Safety information is crucial to guide prescribing and communicate risks in clinical situations that necessitate tetracycline use during pregnancy.
Analysis of secondary outcomes found no increased risk in 10 of 12 major malformation organ system subgroups and none of 16 individual malformations. An observed 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) did not hold up in a sensitivity analysis with follow-up extended to age 3 years.
The authors say the study is notable for being substantially larger than previous studies on tetracycline exposure and MCMs, and for providing new evidence on previously unreported MCM categories.
"Coupled with extensive confounding control and sensitivity analyses to test the robustness of our results, our findings expand on previous evidence pertaining to risks of MCMs with improved precision and covering a broad range of MCM subgroups and individual MCMs," they wrote.
Still, they say that even larger studies are needed to rule out risks for several malformation subgroups and individual malformations.
'Therapeutic orphans'
In an accompanying editorial, John van den Anker, MD, PhD, of Children's National Hospital in Washington, DC, says additional studies are necessary, because questions remain about the safety of tetracyclines, particularly doxycycline, during pregnancy.
"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," he wrote. "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 says priority needs to be given to clinical trials and global registries that focus on the adverse effects of exposure to drugs during different trimesters of pregnancy.
"Until then, every health care practitioner, together with their pregnant patients, needs to weigh the benefits of the treatment against the potential risks for the fetus," he concluded.
