Use of ranitidine is associated with infections in newborns hospitalized in a neonatal intensive care unit: a cohort study

Infections are the major cause of mortality in preterm newborns worldwide [1, 2]. It is well established that the gastric acid secretion is an important non-immune defence barrier for infants against invading pathogens [3, 4]. Although some studies have shown that the use of inhibitors of gastric acid secretion (IGAS) may predispose to infections [5–8] and/or necrotising enterocolitis (NEC) [7, 9], few data are currently available to confirm this association [10]. In addition, most of these studies are based on industrialised countries and there is very limited information on whether these patterns also apply to low- and middle-income populations, where the burden of infection is often highest. Due to the perceived safety and efficacy in older populations, the IGAS therapy has been commonly prescribed off-label in Neonatal Intensive Care Units (NICU) [11, 12]. In this context, we compared the rates of hospital infections, mortality, and NEC between preterm newborns exposed or not to ranitidine therapy admitted to a NICU in Sergipe, Brazil.

Twenty-one (7%) cases of NEC were reported in the patient groups during the study period and ranitidine use was not significantly associated with necrotising enterocolitis (RR = 1.4, 95%IC: 0.6–3.3, p = 0.36).

The mortality rate was significantly higher in neonates who received ranitidine (RR 3.9, 95%CI: 2.1–7.3, p < 0.001). Furthermore, hospitalisation was longer in those exposed to ranitidine (Median (IQR), 36.0 (19.0–59.0) vs 24.0 (14.5–38.0), p < 0.001).

Despite a lack of sufficient evidence demonstrating the safety and efficacy of IGAS use by preterm newborns [10], these drugs have been widely prescribed in an off-label manner to treat prophylaxis or therapy of stress ulcers and gastroesophageal reflux disease (GERD) in NICU. The use of these drugs and its consequences for preterm newborns have raised important questions. However, the majority of the studies evaluating its safety have been performed in developed countries. We performed a retrospective cohort study in order to compare the rates of hospital infections and NEC between preterm newborns exposed or not to ranitidine treatment, admitted to a NICU in a poor area of Northeastern Brazil. In accordance with studies from developed countries, our results showed an association between ranitidine use and an increased risk of infection [6–8, 16, 17] and mortality [7]. However, there was no significant association between the use of ranitidine and NEC.

Gastric acid secretion is one of the main non-immune defenses of newborns against invading microorganisms [8]. According to some studies, increasing the pH of gastric secretion would result in the overgrowth of microorganisms and in predisposition to infection and NEC [18–21]. Sustained inhibition of gastric acid secretion alters the bacterial ecology favouring gastric colonisation by enteric bacteria and may facilitate microbial translocation across barrier due to decreased neutrophil activity [22, 23]. In fact, the use of ranitidine was reported to increase gastric pH within 30 min of administration [24, 25] and its effects not only restrict gastric secretion, but also activate H₂ receptors, modelling the immune response, especially in the production of inflammatory cytokines, and reducing infection control [26–28].

In this study, the presence of GERD was the main indication for the use of ranitidine, followed by prophylaxis, or therapy of stress ulcers. Our study showed that children receiving H2-blocker therapy were more likely to exhibit irritability, sleepiness, and other non-specific symptoms, leading to the false interpretation of GERD persistence and consequently leading to an increase of the drug dosage or the duration of treatment [25]. However, our findings showed that the mean dose of ranitidine administered to newborns is in agreement with other studies (range 1–5 mg/Kg/day) (16), although some studies recommend an intravenous dose of 0.5 mg/kg/day for preterm newborns presenting regular renal function [25, 29]. Furthermore, we found that the time of ranitidine use was not associated with an increase in the infection rate. In this study, the time between the first dose of ranitidine and infection outcome was only 6 days, whereas a study conducted in Croatia reported 18 days [17]. Despite these differences, there is currently no consensus with regard to the safe dose and time usage of IGAS therapy for newborns and further studies are needed.

Some studies have shown that the prolonged use of neonatal intensive care devices by neonates and infants, such as mechanical ventilation, central catheter peripherally inserted and parenteral nutrition dispositive, predispose to infections [30–34]. However, in this study, we have found that these devices were used on newborns receiving ranitidine for longer periods of time. After controlling for confounding variables, we found that ranitidine was independently associated with a risk of infection. Indeed, similar findings were reported by Yildizdas et al. [35].

Although some studies have found an association between the use of ranitidine and an increase in NEC [7, 9], this association was not observed in this study. A possible explanation is that those researchers studied very low birth weight newborns, whereas our population was composed of neonates with a larger variation of birth weight. Therefore, it is possible that the effects of ranitidine on quantitative and qualitative changes of the intestinal microflora composition may be causing NEC in very low birth weight newborns.

In this study, we observed an increase in the hospitalisation time and mortality rate amongst newborns receiving ranitidine. This is consistent with a multi-centre study observing the relationship between ranitidine and unfavourable outcomes [7].

This was a retrospective cohort study based on medical reports and some information were not recorded, such as data on timing, volume and type of enteral feedings, rods count and blood cultures. In addition, at NSLM, the search of fungus in urine to investigate fungal infections in neonates frequently results in no clinical and laboratory improvement after antibiotic use. Despite these limitations, our results are consistent.

In conclusion, ranitidine use was associated with an increased risk of infections and mortality in preterm newborns, but not with NEC. The use of ranitidine in neonates must be further evaluated and used in specific situations. In addition, more studies are needed to increase the information about the use of IGAS in newborns to support the decision of the regulatory agencies authorising and adjusting its use in neonatology.