A study conducted by researchers in the United Kingdom has found that use of macrolide antibiotics during pregnancy is associated with an increased risk of birth defects in children.

The study, published this week in the BMJ, looked at data on more than 100,000 children born in the United Kingdom from 1990 to 2016 to mothers who were prescribed macrolides or penicillins at any time during their pregnancy. The results showed that the association between risk of any birth defect, specifically heart defects, and macrolide use during the first trimester was significantly higher than it was for penicillin use.

Although the findings are observational and do not establish that macrolide antibiotics cause birth defects, they add to growing concerns about use of the drugs during pregnancy. Macrolides are widely used to treat infections in pregnant women with suspected penicillin allergies, but research has shown associations between macrolides and increased risk of heart arrhythmia and cardiovascular mortality, as well as miscarriage in pregnant women.

The authors of the study say the link indicates that alternative antibiotics should be considered for pregnant women.

"Our findings suggest it would be better to avoid macrolides during pregnancy if alternative antibiotics can be used," study co-author Ruth Gilbert, MD, PhD, a professor of clinical epidemiology at University College London's (UCL's) Great Ormond Street Institute of Child Health, said in a university press release.

Increased risk of any malformation

For the study, UCL researchers used data from the UK's Clinical Practice Research Datalink to analyze 104,605 children whose mothers received a prescription for a macrolide (erythromycin, clarithromycin, or azithromycin) or a penicillin at any time during their pregnancy. Children were followed from birth to 14 years, with a median follow-up of 5.8 years.

Two other groups of children—82,314 whose mothers had received a macrolide or penicillin before pregnancy, and 53,735 siblings of children in the study cohort—served as negative controls for the analysis.

The main outcomes the researchers were looking for were major malformations such as heart, genital, and gastrointestinal defects, and neurodevelopmental disorders, including autism and attention deficit hyperactivity disorder. Because of the association between macrolide use and cardiovascular issues, they hypothesized that macrolides might induce fetal cardiac arrhythmia and short-term fetal hypoxia, which can have long-term effects.

Of the children in the study cohort, 8,632 (8.3%) were born to women prescribed a macrolide during pregnancy, and major malformations were recorded in 186 (21.55 per 1,000 live births). Of the 95,973 (91.7%) children born to women who were prescribed a penicillin, a major malformation was recorded in 1,666 (17.36 per 1,000 live births).

After accounting for other factors, including maternal age, drug and alcohol use, and chronic medical treatments, the analysis found that macrolide use in the first trimester was associated with increased risk of any malformation compared with penicillin use (27.65 vs 17.65 per 1,000 live births; adjusted risk ratio [aRR], 1.55; 95% confidence interval [CI], 1.19 to 2.03), specifically cardiovascular malformations (10.60 vs 6.61 per 1,000 live births; aRR, 1.62; 95% CI, 1.05 to 2.51).

"Assuming the associations are causal, we estimate that for every 1,000 mothers prescribed macrolides instead of penicillins during the first trimester, an additional 4.1 (95% confidence interval 0.4 to 9.4) children would have cardiovascular malformations; the corresponding figures for prescriptions during any trimester and genital malformations would be 1.7 (0.4 to 3.5)," the authors of the study write.

Macrolide prescribing in any trimester was associated with a 58% increased risk of genital malformations (4.75 vs 3.07 per 1,000 live births; aRR, 1.58; 95% CI, 1.14 to 2.59). In addition, analysis of specific types of macrolides found that erythromycin in the first trimester was associated with an increased risk of any major malformation compared with penicillin (27.39 vs 17.65 per 1,000 live births; aRR, 1.50; 95% CI, 1.13 to 1.99).

The analysis found no significant associations between macrolides and any other specific malformations or neurodevelopmental disorders. And no significant associations between macrolides and adverse outcomes were found in the control groups.

Antibiotic use during pregnancy common

Use of antibiotics is common in pregnant women, with some estimates indicating as many as one in four women will be prescribed an antibiotic during pregnancy. Although the science on how pregnancy affects the immune system remains unsettled, some expecting mothers are more prone to infections, and pregnancy can make some infections more severe.

The authors say that, given the widespread use of macrolides during pregnancy, international collaboration is urgently needed to further explore the issue.