Overuse of antibiotics early in life may increase the risk for bronchopulmonary dysplasia (BPD) or mortality in very premature infants, a national cohort study from China found.

Among 6,510 such newborns considered to be at low risk for early-onset sepsis, prolonged exposure to antibiotics in the first week of life was associated with a 23% higher odds of moderate to severe BPD or death compared with no exposure (adjusted odds ratio [OR] 1.23, 95% CI 1.01-1.50) and a 40% higher odds compared with short-term antibiotic exposures (aOR 1.40, 95% CI 1.15-1.71).

Furthermore, any exposure to broad-spectrum antibiotics during this timeframe was associated with a 27% higher odds of moderate to severe BPD or mortality compared with no antibiotic exposure (aOR 1.27, 95% CI 1.04-1.55), reported Xiaolu Ma, MD, PhD, of Zhejiang University School of Medicine in Hangzhou, and coauthors in JAMA Network Open.

Risk for moderate or severe BPD on its own was also elevated with antibiotic overuse, the study found. In analyses of survivors at 36 weeks’ gestational age, the BPD risk was higher with prolonged antibiotic exposure (aOR 1.40 versus no exposure, 95% CI 1.14-1.73) and with any use of broad-spectrum antibiotics (aOR 1.24, 95% CI 1.01-1.52).

Given their immature immune systems and reliance on invasive life support, very preterm infants are at greater risk for early-onset sepsis and often receive empirical antibiotics as a result, explained Ma and co-authors.

For infants at low risk for early-onset sepsis, the American Academy of Pediatrics recommends discontinuation by 36 to 48 hours if blood cultures are sterile. In practice, that doesn’t always happen, with a 2017 study showing that more than a third of U.S. newborns received a prolonged course of antibiotics despite being considered low-risk.

Edward Shepherd, MD, of Nationwide Children’s in Columbus, Ohio, described the efforts among clinicians to reduce antibiotic overuse as a much-needed “cultural shift,” and said the findings from Ma’s team “really backs up” what many have said for a long time.

“While we used to think of antibiotics as a miracle cure for almost everything, in reality they are good for one very specific thing, and that’s killing specific bacteria,” he told MedPage Today.

“If you use them for any other purpose, the side effects are much more likely to be predominant than any positive effects,” said Shepherd, who was not involved in the research.

The study from Ma and colleagues is the latest to find links between prolonged antibiotic use in premature infants and increases in mortality and adverse health outcomes. But findings had been mixed when it came to BPD, the most common serious morbidity of preterm birth, which is associated with long-term adverse consequences, including increased susceptibility to respiratory infections and development of chronic obstructive pulmonary disease.

The authors said that clinicians should consider the disruption to the microbiome, and potential downstream consequences, when considering whether antibiotics are appropriate to prescribe.

“Research has shown that early antibiotic exposure can disrupt the preterm microbiome, thereby precipitating adverse outcomes like BPD by influencing systemic inflammation via the gut-lung-brain axis,” wrote Ma and co-authors. “Additionally, prolonged use of broad-spectrum antibiotics is associated with an increased risk of colonization by antibiotic resistant organisms such as cephalosporin-resistant gram-negative bacteria, vancomycin-resistant Enterococcus, and carbapenem-resistant organisms.”

Their analysis focused on 6,510 very preterm infants (<32 weeks’ gestational age or <1.5 kg at birth) at low risk of early-onset sepsis in the Chinese Neonatal Network. To be categorized as low risk, infants needed to be born via c-section, have no membrane rupture at delivery, and lack clinical features of chorioamnionitis. Those with early sepsis or major congenital anomalies were excluded, among other criteria.

Overall, 62.2% received a prolonged antibiotic course (5-7 days), 17.4% received a short course (1-4 days), and 20.3% had no exposure. Among the patients treated with antibiotics, 79% received broad-spectrum antibiotics (extended-spectrum penicillins with beta-lactamase inhibitors, third- or fourth-generation cephalosporins, carbapenems, linezolid, and vancomycin), 17.1% narrow-spectrum antibiotics, and 3.9% received antifungals or other antibiotics.

Significant differences in baseline characteristics were seen between groups, with infants in the prolonged antibiotic treatment group having a younger gestational age (5.5% under 28 weeks), lower birth weight (14% under 1 kg), and lower incidence of small for gestational age (28%).

“Additionally, these infants were more likely to require intubation at birth, mechanical ventilation during the first week of life, treatments involving surfactant and nitric oxide, as well as medical treatment for [patent ductus arteriosus],” the study authors noted, and their mothers “tended to be older and less likely to have received corticosteroids or magnesium sulfate prior to delivery.”

As such, models adjusted for those factors along with sex, multiple pregnancy, gestational diabetes, hypertension, preeclampsia, or eclampsia.

Among the limitations, the researchers cited the observational design of the study, the exclusion of infants with severe illnesses, as well as the multifactorial nature of BPD development.

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    Elizabeth Short is a staff writer for MedPage Today. She often covers pulmonology and allergy & immunology. Follow


The study was supported by the National Key Research and Development Program of China, the Shanghai Science and Technology Commission, and the Canadian Institutes of Health Research.

Study authors and Shepard reported no disclosures.

Primary Source

JAMA Network Open

Source Reference: Shi W, et al “Early antibiotic exposure and bronchopulmonary dysplasia in very preterm infants at low risk of early-onset sepsis” JAMA Netw Open 2024; DOI: 10.1001/jamanetworkopen.2024.18831.

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