Key Messages
- Reflux is common in preterm infants
- The current evidence neither supports nor refutes the safety and efficacy (usefulness) of proton pump inhibitors (PPIs) for the treatment of reflux in preterm infants.
What is gastroesophageal reflux, and how does it differ from gastroesophageal reflux disease?
Gastroesophageal reflux happens when the stomach contents flow back into the esophagus (canal joining throat to stomach). It is common in a newborn. Premature infants are more likely to experience reflux because they have a looser connection at the point where the stomach joins the esophagus. They often have feeding tubes in place, which go from their mouth or their nose into the stomach, which can open this junction further.
Gastroesophageal reflux disease (GERD) is considered when reflux leads to symptoms, such as poor weight gain, feeding intolerance, and pain.
GERD may cause other symptoms in preterm infants, such as apnea (pause in breathing), bradycardia (slow heart rate), or desaturation (drop in amount of oxygen in blood). The upper digestive tract contains sensors that can cause a drop in heart rate or oxygen when activated. These are more sensitive in preterm infants, and reflux may trigger them.
How is gastroesophageal reflux disease treated ?
The most common treatments for GERD are: changing the position of the infant during or after feeding; changing the type or consistency of their formula; or using medicine that reduces the acid in their stomach contents. PPIs are widely used medicines for this population, but they have side effects, such as increased risk for infection, inflamed bowels, changes in bone density, and childhood obesity. There are not many studies that evaluate how useful and safe PPIs are for treating GERD in preterm infants.
What did we want to find out?
How safe and useful are PPIs in preterm infants diagnosed with GERD?
What did we do?
We searched for studies in the medical literature that assessed the use of PPIs in preterm infants who were hospitalized and had GERD.
What did we find?
After screening 1217 articles, two studies met our criteria. They included a total of 62 preterm infants, whose age ranged from 31 weeks' to 36 weeks' gestation. One study randomized (all infants had an equal chance of receiving either treatment) the infants to receive PPI or placebo (fake medicine) for seven days, and then switched treatments for another seven days. The other study randomized infants to receive PPI or placebo for 14 days. The studies did not report on many of our outcomes of interest, and we were unable to pool the data from the outcomes on which they did report.
Main Results
The two studies showed little or no reduction in GERD-related events, such as apnea, bradycardia, and desaturation with PPI use, but we are uncertain about the results.
Quality and limitations of the evidence:
One study was sponsored and run by the drug company that made the PPI. The other study was a cross-over study, which did not allow enough time between treatments for the medicines to clear the infants' systems. There were limited data for any of the outcomes.
How up to date is this evidence?
This evidence is up-to-date as of October 2023.
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.
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.
To assess the benefits and harms of PPIs for the treatment of preterm infants with diagnosed or suspected GERD.
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.
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.
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).
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).