Ceftriaxone-Associated Biliary and Cardiopulmonary Adverse Events in Neonates: A Systematic Review of the Literature

Paediatr Drugs. 2017 Feb;19(1):21-34. doi: 10.1007/s40272-016-0197-x.


Background: Ceftriaxone is a third-generation cephalosporin with broad-spectrum activity against both Gram-positive and Gram-negative bacteria. Despite its effectiveness, its use for the treatment of infections in neonatal patients has been limited because of concern about its potential toxicity.

Objective: Our aim was to review the literature for an association between ceftriaxone and cardiopulmonary events, hyperbilirubinemia, and pseudolithiasis among neonates.

Methods: We searched PubMed and EMBASE and included studies that evaluated ceftriaxone safety in neonates. Study bias was evaluated in the following domains: exposure measurement, outcome measurement, attrition, generalizability, confounding, statistical analysis, and reporting.

Results: We included nine studies regarding ceftriaxone side effects, primarily spontaneous reports, published case reports, and small case series. Reports of bilirubin displacement attributed to ceftriaxone included increases in serum bilirubin necessitating antibiotic change in a subset of infants after administration of ceftriaxone. One study described self-resolving biliary sludge after ceftriaxone administration in six of 80 infants. Cardiopulmonary adverse events included a report of eight cardiopulmonary events related to concomitant ceftriaxone-calcium infusion, including seven infant deaths. Additional cardiopulmonary events reported included perinatal asphyxia, pulmonary hypertension, and thrombocytosis. However, the available literature had small sample sizes, poor external validity, and inconsistent outcome ascertainment methods, which made it impossible to estimate the magnitude of risk.

Discussion: Concomitant administration of intravenous ceftriaxone and calcium-containing solutions should be avoided in neonates. However, further controlled studies are needed to assess whether bilirubin displacement associated with the use of ceftriaxone is clinically relevant, particularly in healthy term and near-term neonates with mild hyperbilirubinemia.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Administration, Intravenous
  • Anti-Bacterial Agents / adverse effects*
  • Bilirubin / blood
  • Ceftriaxone / adverse effects*
  • Humans
  • Infant, Newborn


  • Anti-Bacterial Agents
  • Ceftriaxone
  • Bilirubin