Study Suggests Women Should Avoid Macrolides During First Trimester

Macrolide use during the first trimester was linked to an increase in major malformations—specifically cardiovascular malformations—in children.

A new analysis of more than 100,000 children from the United Kingdom is revealing more about the potential dangers associated with use of macrolide antibiotics during early pregnancy.

Results of the analysis, which examined erythromycin, clarithromycin, and azithromycin, suggested macrolide monotherapy during the first trimester was associated with an increase in major malformations—including genital and cardiovascular malformations—compared to children born to mothers who used penicillin.

With multiple countries advising against the use of some or all macrolide antibiotics in early pregnancy, investigators from the University College of London conducted a retrospective cohort study using a primary care database of 104,605 children. As macrolide antibiotics are often prescribed in patients with a penicillin allergy, investigators sought to determine whether macrolide antibiotics was associated with an increase in major malformations and 4 neurodevelopment disorders.

The 104,605 children included in the study were born from 1996-2016 and had mothers who were prescribed 1 of the 3 aforementioned macrolide monotherapy or penicillin monotherapy between the fourth gestational week and delivery. For comparison, a pair of negative control cohorts were established by the investigators.

The first cohort was children of mothers prescribed one macrolide or penicillin monotherapy 50-10 weeks prior to their last menstrual period and not included in the cohort. The second cohort was comprised of siblings of children in the study cohort.

Of the 104,605 children included in the analysis, 8.3% were born to mothers prescribed macrolide monotherapy and 95,973 were born to those prescribed penicillin monotherapy during pregnancy—the median follow-up time was 5.8 years after birth.

In the first negative control cohort, 11,874 of the 82,314 were born to mothers prescribed macrolides and the remaining 70,440 were born to mothers prescribed penicillin. In the siblings cohort, 4512 were siblings of children prenatally exposed to macrolides and 49,223 were siblings of children prenatally exposed to penicillin.

For the purpose of the analysis, investigators defined monotherapy as 1 or more consecutive prescriptions for a single antibiotic separated by no more than 30 days and uninterrupted by prescriptions for other antibiotics—antibiotic prescription were identified through the British National Formulary.

In the primary analysis, the prevalence of major malformations was 27.7 per 1000 livebirths among mothers prescribed macrolide during the first trimester and 19.5 per 1000 livebirths in mothers prescribed macrolide in the second to third trimester. In the penicillin group, the rate was 17.7 per 1000 livebirths if prescribed during the first trimester and 17.3 per 1000 live births if prescribed during the second to third trimester.

Results of the analysis indicated macrolide prescribing in the first trimester was linked to an increased risk of any malformation (aRR: 1.55, 95% CI, 1.19-2.03) and an even greater risk of cardiovascular malformations 10.6 v 6.6 per 1000 livebirths; aRR: 1.62, 95% CI, 1.05-2.51). Conversely, macrolide prescribing later in pregnancy was not associated with an increased risk of any major malformation (aRR: 1.13, 95% CI, 0.94-1.36).

Investigators noted macrolide prescribing in any trimester was associated with an increased risk of genital malformations and a borderline association was found with prescribing during the second and third trimester and gastrointestinal malformations. No associations were found between macrolide prescribing during pregnancy and cerebral palsy, epilepsy, ADHD, or autism spectrum disorder.

Based on the results of their study, investigators suggest clinicians should use caution if prescribing macrolides during pregnancy and, if possible, should seek alternative antibiotics until the impact of macrolide on adverse child outcomes is further understood.

"If the associations are shown to be causal, these findings suggest that an additional 4 children would be born with cardiovascular malformations for every 1,000 children exposed to macrolides instead of penicillins in the first trimester of pregnancy," said lead investigator Heng Fan, PhD candidate at University College London Great Ormond Street Institute of Child Health, in a statement.

This study, “Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study,” is published in BMJ.