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Ranitidine therapy in neonates requires caution

Terrin G. Pediatrics. 2011;doi:10.1542/peds.2011-0796.

Using ranitidine to address symptoms of gastric distress in very low birth weight infants may contribute to increased mortality and necrotizing enterocolitis in this population of patients, according to study results published online this week.

Gianluca Terrin, MD, PhD, of the department of women’s health and territorial medicine at the University La Sapienza in Rome, and colleagues looked at data on 274 very low birth weight infants born between 24 and 32 weeks at four Italian neonatal ICUs. Ninety-one of the infants received ranitidine for peptic disease or suspected gastroesophageal reflux disease, and the remainder of the infants did not receive ranitidine.

The researchers said the mortality rate was “significantly higher in newborns receiving ranitidine (9.9% vs. 1.6%),” as was the rate of necrotizing enterocolitis. Also, the rate of necrotizing enterocolitis was sixfold higher in the group of children receiving the medication.

Terrin and colleagues said 37% of the infants who received ranitidine developed infections, and about 10% of the infants who were not treated with ranitidine did not develop infections, with sepsis being most commonly reported.

The researchers urged additional studies into the reasons for the increased risks associated with ranitidine and the “possible prophylactic measures that could be taken to prevent them.” They said although ranitidine is off-label in this age population, the medication’s use has been increasing in recent years.

Disclosure: The researchers report no relevant financial disclosures.

This multi-center prospective 18-month study involving very low birth weight (VLBW) neonates receiving care at four Italian neonatal intensive care units provides provocative evidence for the assessment of use of ranitidine in this population.

In addition to increased rates of sepsis, defined as the isolation of an organism from a blood culture in combination with clinical signs of illness, among the recipients of ranitidine, there was also a predominance of gram-negative isolates. There was a trend among the neonates with sepsis who were not exposed to ranitidine to have coagulase negative staphylococci and Candida isolates. Although the total numbers of infants with pneumonia and urinary tract infections in both the ranitidine receipt and non-receipt groups was less than 10, there appeared to be a greater risk for each of these manifestations among the neonates who received ranitidine. The isolation of Esherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa at greater rates from the infants receiving ranitidine lends plausibility to the hypothesis that hypochlorhydria leads to perturbation of intestinal flora resulting in septic episodes. The increased rates of necrotizing enterocolitis (NEC) and mortality among the neonatal ranitidine recipients also supports the potential association of ranitidine with severe adverse outcomes in this population.

Although not described in detail, it would have been interesting to know if there was a difference in enteral feed composition, especially with respect to receipt of human milk. Additionally, a description of the selection and duration of antimicrobials to treat infectious episodes and NEC would have been useful. Human milk consumption has been associated with prevention of infection and NEC, while antimicrobial administration has been associated with the perturbation of gastrointestinal flora.

This study provides important preliminary information regarding potential adverse effects of use of histamine antagonists in VLBW neonates. While gastric protection and management of gastroesophageal reflux disease is important, the authors suggest that a re-evaluation of ranitidine to accomplish these goals be considered. Furthermore, additional prospective evaluations in larger populations of at risk neonates are needed to substantiate the findings of this study.

Andi L. Shane, MD MPH, MSc
Infectious Diseases in Children Editorial Board

Disclosure: Dr. Shane reports no relevant financial disclosures.

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