Safety and efficacy of proton pump inhibitors in preterm infants with gastroesophageal reflux disease.

Background: Although physiological reflux is seen in nearly all newborns to varying degrees, symptoms can be severe and cause gastroesophageal reflux disease (GERD). In preterm infants, one symptom that is often attributed to GERD is apnea and associated cardiorespiratory events, such as bradycardia and oxygen desaturation. Although the relationship between GERD and apnea, bradycardia, and desaturation events remains a subject of ongoing investigation, trials of agents that reduce gastric acidity, such as proton pump inhibitors (PPI), have been conducted to assess the effect of these agents on GERD.

Objectives: To assess the benefits and harms of PPIs for the treatment of preterm infants with diagnosed or suspected GERD.

Search Methods: We searched CENTRAL, MEDLINE, Embase, two trial registries, and Epistemonikos in October 2023. We checked reference lists of included studies, and studies and systematic reviews in which the subject matter was related to the intervention or population examined in this review.

Selection Criteria: We included randomized controlled trials, quasi-randomized controlled trials, cross-over trials, and cluster-randomized trials that assessed the use of PPIs (including esomeprazole, lansoprazole, omeprazole, pantoprazole, or rabeprazole) alone or in combination. Infants had to receive treatment for a minimum of three days. We considered the following comparisons: (1) PPIs versus no treatment, (2) PPI versus positioning changes (elevated head of bed or prone positioning), (3) PPI versus dietary changes (thickened feeds). We excluded studies examining alginates and histamine receptor blockers. Studies including other non-pharmacological interventions for GERD were included if these interventions were available to infants in all study groups.

Data Collection And Analysis: Two review authors independently identified eligible trials, reviewed the methodological quality of each trial, and extracted data on prespecified outcomes. Data were compared and differences resolved. We used standard methods of Cochrane Neonatal to synthesize data using relative risk (RR), risk difference (RD), and mean difference (MD).

Main Results: After screening 1217 articles, only two studies, enrolling a total of 62 infants, met our criteria. Both studies compared the use of PPIs to no treatment (placebo). One study included ten infants with a mean gestational age of 36.1 ± 0.7 weeks, who were treated with seven days of PPI or placebo, and then crossed over to the other study arm for seven days, with gastric pH monitoring performed at the end of each week. The other study included 52 infants with a mean gestational age of 31 weeks, who were randomized to a PPI or placebo for 14 days, with various outcomes measured at baseline and after 14 days. Both studies were judged to be at low risk of bias. Only one study (N = 52) reported the primary outcome, cardiorespiratory events. The evidence is very uncertain about the effect of PPIs on cardiorespiratory events (MD 6.14 lower, 95% CI 44.51 lower to 32.23 higher). The evidence is very uncertain for the reported secondary outcome measures, including apnea at the end of treatment (MD 0.30 lower, 95% CI 0.93 lower to 0.33 higher), bradycardia at the end of treatment (MD 1.89 higher, 95% CI 1.11 lower to 4.89 higher), desaturation at the end of treatment (MD 7.72 lower, 95% CI 45.86 lower to 30.42 higher), choking at the end of the treatment (MD 0.96 higher, 95% CI 1.88 lower to 3.80 higher), irritability at the end of treatment (MD 0.02 higher, 95% CI 11 lower to 10.96 higher), and vomiting at the end of treatment (MD 0.34 higher, 95% CI 3.15 lower to 3.83 higher). The study was prematurely discontinued due to poor enrollment. One study (N = 10) reported a marked reduction in the percentage of time spent with esophageal acid exposure, with pH < 4. However, there was no effect on the frequency of symptoms. The study sample precludes the ability to extrapolate any significant data. Neither study reported data on length of stay or parental satisfaction. There were insufficient data to perform a meta-analysis. No trials addressed the issue of PPI versus positioning changes, or PPI versus dietary changes (thickened feeds).

Authors' Conclusions: Although widely used, there are insufficient data regarding the benefits and harms of proton pump inhibitors in preterm infants with gastroesophageal reflux disease. The most limiting factor was the paucity of studies on preterm infants. Even the studies that were included in this review were not limited to preterm infants. Hence, further studies are needed to address the safety and efficacy of proton pump inhibitors for the treatment of diagnosed or suspected gastroesophageal reflux disease in preterm neonates.