Ranitidine-Associated Risk for Death in Premature Newborns

Laird Harrison

December 12, 2011

December 12, 2011 — Very-low-birth-weight newborns given ranitidine, a therapy for stress ulcers and gastroesophageal reflux disease (GERD), are about 6 times more likely to die than similar newborns not given the drug, according to the results of a new study published online December 12 in Pediatrics.

Gastric acid kills pathogens, and by inhibiting its secretion, ranitidine increases the risk for infection, said researchers.

"Ranitidine should be administered with care in preterm infants because of the risk of severe infectious disease, [necrotizing enterocolitis], and fatal outcome," concluded researchers from 9 centers in Italy, led by Gianluca Terrin, MD, PhD, from the Department of Women's Health and Territorial Medicine, University La Sapienza, Rome, Italy.

The US Food and Drug Administration has not approved ranitidine for use in preterm infants, but off-label use in this population is increasing, the researchers said.

The current study is the first multicenter prospective study on morbidity and mortality associated with ranitidine in very-low-birth-weight newborns.

To test the safety of this application, the researchers enrolled 274 consecutively observed newborns with birth weights ranging between 401 and 1500 g, or a gestational age between 24 and 32 weeks, in 4 Italian neonatal intensive care units.

Forty-two of these infants received ranitidine to prevent stress-induced peptic disease. Another 49 received the drug because of suspected GERD. The remaining 183 newborns did not receive ranitidine.

The 2 populations did not differ significantly in their demographic or clinical characteristics. Moreover, multivariate analyses showed that the prescription of ranitidine by physicians was not affected by the infants' gestational age, birth weight, sex, Apgar score, Critical Risk Index for Babies score, central vascular access, or mechanical ventilation.

Thirty-four infants who received ranitidine developed infections (37.4%), whereas 28 of those not exposed to ranitidine did (9.8%), which was a significant difference (P < .001). Sepsis was the most common infection, affecting 25.3% of the infants who received ranitidine compared with 8.7% of the infants who did not receive the drug. Pneumonia (4.4% vs 0.5%) and urinary tract infections (7.7% vs 0.5%) made up the remainder of the infections, although those differences did not reach statistical significance. The duration of ranitidine treatment did not affect the risk for infection.

The infants who received ranitidine suffered necrotizing enterocolitis at a rate of 9.8% vs 1.6% among the infants who did not receive the drug (P = .003).

Infants who received ranitidine spent a median of 52 days in the hospital compared with 36 days for the infants who did not (P = .001).

Finally, 9.9% of the infants receiving ranitidine died vs 1.6% of those who did not receive the drug (P = .003).

"The results of this study suggest that ranitidine should be administered only after a careful consideration of the risk-benefit ratio," Dr. Terrin and colleagues conclude.

Additional studies are warranted to investigate the reasons for the increased risks associated with ranitidine. Although it appears that the drug changes the gastric environment in a way that favors pathogens, such as Escherichia coli and Klebsiella pneumonia e, both of which were documented in this study, it may also suppress immune defenses, including the production of inflammatory cytokines, and disrupt the Th1-Th2 balance, the researchers speculated.

The researchers have disclosed no relevant financial relationships.

Pediatrics. Published online December 12, 2011. Full text

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