USE OF MACROLIDES IN PREGNANCY

The macrolide antibiotics include azithromycin, clarithromycin, erythromycin, spiramycin and telithromycin. Macrolides have an antibacterial spectrum similar to that of penicillin and are thus considered an alternative in penicillin-allergic patients. Indications include sinusitis, otitis media, pharyngitis, tonsillitis, bronchitis, skin and soft tissue infection. Azithromycin is also used in the treatment of chlamydia, and clarithromycin in the eradication of Helicobacter pylori.

The majority of studies investigating malformation risk following maternal macrolide use in pregnancy do not provide evidence of an association. However, a small number of individual studies investigating both macrolides as a class and erythromycin specifically have described increased risks of both overall malformation and cardiac malformation. A small number of individual studies have also described as yet unconfirmed associations with other specific anomalies, including genital, musculoskeletal and gastrointestinal defects. However, the results of all of these studies may have been impacted by methodological biases and/or confounding by indication. Furthermore, the increase in absolute malformation risk indicated by these studies is small.

The available evidence relating to miscarriage risk following macrolide use in pregnancy is also conflicting, and although some studies have described increased risks, these findings may have been impacted by methodological biases and/or confounding by indication. Further research is therefore required.

The available data relating to risks of preterm delivery, low birth weight and neonatal complications do not suggest increased risks for macrolides as a class or for specific macrolides. A theoretical risk of pyloric stenosis in the neonate following macrolide exposure during pregnancy has not been supported by several large studies.

Data regarding other neonatal and longer term outcomes are absent or extremely limited. Results from two randomised controlled trials which investigated offspring neurodevelopment and cerebral palsy risk following antibiotic use in the management of spontaneous preterm labour or premature rupture of membranes (PROM) are conflicting, although an electronic health record study has since reported a higher risk of cerebral palsy and epilepsy amongst children of women treated with macrolides during pregnancy compared to those of women receiving penicillin. Nonetheless, at the time of writing, the Royal College of Obstetricians and Gynaecologists (RCOG) advise routine intrapartum antibiotic prophylaxis (IAP) for all women in preterm labour, with or without PROM. Benzylpenicillin should be used preferentially, but substituted for a cephalosporin in patients with a non-severe penicillin allergy, or vancomycin where the allergy is severe. The National Institute for Health and Care Excellence (NICE) guidelines also state that women with pre-labour PROM should be offered oral erythromycin (250mg, 4 times a day) for a maximum of 10 days or until the woman is in established labour (whichever is sooner), with oral penicillin offered to patients who cannot tolerate erythromycin.

Although the majority of the available data do not provide evidence that macrolide use in pregnancy increases the risk of adverse pregnancy outcome, a limited number of studies have described small increased risks of malformation and miscarriage. Macrolide use in pregnancy should therefore be reserved for compelling indications where there are no suitable alternatives with adequate pregnancy safety data, and should only be used if the benefit of treatment is expected to outweigh any small increased risks which may exist.

Where possible, the results of culture and sensitivity tests should be available before making a treatment choice in accordance with local prescribing guidelines. If a macrolide is indicated, erythromycin is the preferred choice during pregnancy because there is more documented experience of its use than for other macrolides. 

Exposure to a macrolide antibiotic at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.