Macrolides During Pregnancy Tied to Higher Birth Defects Risk

Children whose mothers were prescribed macrolide antibiotics during pregnancy had a higher risk of malformations compared with children whose mothers were prescribed penicillin, according to a population-based cohort study.

Mothers that were prescribed macrolide antibiotics — such as erythromycin, clarithromycin, or azithromycin — during the first trimester of pregnancy had offspring more likely to develop a major malformation versus mothers that were prescribed penicillin (adjusted risk ratio 1.55, 95% CI 1.19-2.03), reported Heng Fan, of the Great Ormond Street Institute of Child Health at University College London, and colleagues.

Compared with penicillin, macrolide prescribing in the first trimester was specifically associated with a higher risk of cardiovascular (CV) malformations (10.60 vs 6.6 per 1,000, aRR 1.62, 95% CI 1.05-2.51), they reported in The BMJ.

Macrolides are a class of antibiotics used to treat bacterial infections, and are often prescribed as an alternative for patients allergic to penicillin. Although macrolides are commonly prescribed, and erythromycin specifically is considered safe for pregnant women, Fan said that this research provides further evidence that providers should prescribe macrolides with caution.

“There has been evidence of rare but serious outcomes of macrolide use, especially in unborn children,” Fan told MedPage Today in an email. Adverse outcomes associated with macrolide use include miscarriage, congenital malformations, and cerebral palsy, although evidence for the latter two outcomes is less consistent. Fan added that policies regarding the safety of macrolide use during pregnancy also vary.

Although the outcomes of macrolide use in unborn children can be serious, Fan said the risk of major malformations is low. “Women need to know that untreated bacterial infections during pregnancy are far more damaging to the unborn baby,” Fan emphasized, adding that while women should not stop taking antibiotics when needed, alternatives to macrolides are recommended.

The investigators aimed to address uncertainties in current research by comparing the risk of major malformations and neurodevelopmental disorders in children whose mothers were prescribed macrolides during pregnancy to those whose mothers were prescribed penicillin. Because macrolides are often prescribed as an alternative for patients allergic to penicillin, the authors compared the two classes of antibiotics to mitigate any confounding due to infection.

Fan and colleagues obtained data from the U.K. Clinical Practice Research Datalink, a primary care database that includes information about prescriptions. They assessed for malformations within five systems (nervous, CV, gastrointestinal, genital, and urinary). In addition, they measured risk of four neurodevelopmental disorders: cerebral palsy, epilepsy, attention deficit-hyperactivity disorder (ADHD), and autism spectrum disorder (ASD).

The group also conducted subgroup analyses by macrolide subtype and duration of treatment.

The study included nearly 105,000 children born from 2010 to 2016 to mothers that were prescribed either one episode of macrolide monotherapy, or one episode of penicillin monotherapy, from week 4 of pregnancy until delivery. Researchers defined an episode of monotherapy as one or more prescriptions of a single antibiotic that occurred within a month and was not in conjunction with any other drug prescriptions. They began evaluation at 5 weeks gestation — when fetal organs begin to form — and followed children up to either age 14, death, or end of follow-up in June 2016.

Mothers of more than 30% of children were prescribed at least one antibiotic during pregnancy, researchers found. Penicillin prescriptions accounted for about 69% of these prescriptions, and macrolides around 10%. There were approximately 8600 children born to mothers prescribed macrolides, and 96,000 to mothers prescribed penicillin.

Major malformations occurred in 27.7 per 1,000 children whose mothers were prescribed macrolides in the first trimester, and in 19.5 per 1,000 when prescribed in the second to third trimester. The prevalence of malformations among children whose mothers were prescribed penicillin in the first trimester was 17.7 per 1,000.

Children whose mothers were prescribed macrolides during any trimester had an increased risk of genital malformations (aRR 1.58, 95% CI 1.14-2.19), although findings were not significant when restricted to first trimester prescribing.

In a macrolide subgroup analysis, researchers found that erythromycin prescribing in the first trimester was associated with an increased risk of any major malformation (aRR 1.50, 95% CI 1.13-1.99). There were no significant findings for clarithromycin and azithromycin.

There was no association between macrolide prescribing during pregnancy and presence of cerebral palsy, epilepsy, ADHD, or ASD.

Fan and colleagues acknowledged that a key weakness of the research was its limited ability to examine exposure to macrolides during known development periods for specific malformations and neurological disorders. In addition, they said that their analysis of antibiotic prescribing — as opposed to dispensing or use — may have limited the findings.