What are the effects of macrolide (antibiotics) use in preventing long-term lung disease in preterm babies?

Key messages

• Bronchopulmonary dysplasia is a long-term lung disease that is common in preterm infants with underdeveloped lungs. The safety and efficacy (usefulness) of giving macrolides (a type of antibiotic) to very preterm (born before 32 weeks of pregnancy) or very low-birthweight (< 1500 g) infants who require invasive breathing support (a tube in their mouths) in the first 72 hours of life to prevent bronchopulmonary dysplasia is unclear.

• Future studies are needed looking at the effects of macrolides on long-term outcomes and their use in other types of infants at risk of, or with bronchopulmonary dysplasia. There is also a need for further research into the length of time macrolides should be given.

What is bronchopulmonary dyplasia?

Very preterm infants and very low-birthweight infants are at risk of developing bronchopulmonary dysplasia, a long-term lung disease that is common in preterm infants with underdeveloped lungs. This can be mild to severe and involves the swelling (inflammation) of the air sacs of the lung, making it hard to breathe. Infants may need oxygen at home and are prone to recurrent chest infections and asthma as young children. Infants who are born very early and who require a tube in their windpipe to breathe are at increased risk of developing long-term lung inflammation and lung disease.

How is bronchopulmonary dyplasia prevented?

One way to help prevent chronic lung disease in infants may be to give those needing breathing tubes soon after birth a course of macrolides. Macrolides are a group of antibiotics that have anti-inflammatory effects on the lungs. Macrolide drugs include azithromycin, erythromycin, and clarithromycin. These have been used in other lung diseases, including shortness of breath and scarring of lung tissue (emphysema) or restricted airflow and breathing problems (chronic obstructive pulmonary disease) in adults, and thick, sticky mucus builds up in the lungs (cystic fibrosis) in children, to help breathing and chest symptoms of cough and wheeze.

What did we want to find out?

We wanted to know whether macrolide administration might benefit very preterm and very low-birthweight infants. Specifically, we wanted to know the effects of macrolide administration (either into a vein or into the stomach) compared to placebo (dummy treatment) or no treatment on the following outcomes.

• Bronchopulmonary dysplasia

• Death before discharge

• Stomach upsets (diarrhoea and vomiting)

• Liver dysfunction

• Heart arrhythmias (irregular heartbeats)

• Pyloric stenosis (thickening and obstruction of the stomach outlet into the intestines)

• The need for steroids to treat lung inflammation in the period after the infant's birth

What did we do?

We searched for studies that examined macrolide administration compared with placebo or no treatment in very preterm or very low-birthweight infants (or both) requiring ventilation (a breathing tube in their windpipe) soon after birth, for the prevention of bronchopulmonary dysplasia. We compared and summarised the results of the included studies and rated our confidence in the evidence based on factors such as study methods and sizes.

What did we find?

We found six studies including 1108 preterm infants comparing macrolide administration with placebo or no treatment in ventilated infants soon after birth. There are five ongoing studies that have not been published or completed yet. One further study is awaiting classification, as we need outcome data from the authors.

Five of the six included studies administered azithromycin intravenously (through a vein): it was given for six weeks in two studies (intravenously until on full feeds, then enterally (into the stomach via a feeding tube)); for 10 days in one study; for five days in one study; and for three days in the remaining study. The sixth study administered erythromycin intravenously for a seven-day course.

Main results

Giving very preterm and very low-birthweight infants macrolides (specifically azithromycin) compared to placebo or no treatment, when they require a breathing tube soon after birth, may:

• make little to no difference to the diagnosis of bronchopulmonary dysplasia;

• cause a slight reduction in death before discharge home from hospital;

• reduce stomach upsets;

• make little to no difference to other unwanted effects of macrolides including liver dysfunction, heart arrhythmias, or pyloric stenosis;

• reduce the need for steroids to treat lung inflammation in the period after the infant's birth.

What are the limitations of the evidence?

We have little confidence in most of the evidence, meaning future research in this area could change our conclusions. Three main factors reduced our confidence in the evidence. Firstly, our strict inclusion criteria limited the number of studies and subsequent number of infants included. Secondly, the studies spanned 30 years, during which time there have been significant advances in the care of sick babies and the definitions of lung disease used, which limited our ability to find meaningful results. Finally, five of the six studies used azithromycin, and one study used erythromycin, so we may not be able to say if the results apply to other macrolides.

How up-to-date is this evidence?

The evidence is current to June 2025.