Many Fragile Neonates Still Receive Acid-Suppressing Medications Interview with:

Jonathan Slaughter, MD, MPH Assistant Professor of Pediatrics Center for Perinatal Research Nationwide Children's Hospital/The Ohio State University Columbus, OH 43205

Dr. Jonathan Slaughter

Jonathan Slaughter, MD, MPH
Assistant Professor of Pediatrics
Center for Perinatal Research
Nationwide Children’s Hospital/The Ohio State University
Columbus, OH 43205 What is the background for this study?

Dr. Slaughter:   Increasing data has emerged over the last decade showing potential harm following acid suppression use in newborns, older children, and adults.  There are virtually no published data that show acid suppression via histamine-2-receptor antagonists (H2RAs) or proton-pump inhibitors (PPIs) is effective for gastroesophageal reflux disease (GERD) treatment or for other indications (stress ulcer prophylaxis, post-operative acid suppression) in healthy or sick newborns. Given the potentially limited effectiveness of these medications and increasing safety concerns following H2RA/PPI use in infants, we wanted to evaluate the frequency and duration of H2RA/PPI use among infants hospitalized within US children’s hospital neonatal intensive care units (NICUs) to determine if these drugs appeared to be overused and if use appears to have changed over time.  We also evaluated neonatal diagnoses associated with acid suppression to identify targets for future studies that may evaluate the usefulness of acid suppression in neonates following a given diagnosis. What are the main findings?

Dr. Slaughter: Our main finding was that despite a lack of published evidence for improved outcomes following their administration and increasing concerns for adverse effects, H2RAs/PPIs were prescribed to 23% of neonates in US children’s hospitals between 2006-2013, often to discharge. There was a wide degree of variation in the overall use of acid suppression treatment in children’s hospital NICUs and even variation in the most prescribed drug class, H2RA or PPI, among hospitals.  We think most of this practice variation is due to physician and institutional preferences given the lack of data on H2RA/PPI use in neonates.

A positive finding was that the volume of H2RA/PPI prescribing in neonatal intensive care units (NICUs) did decrease during the period we studied. It also appears that, on-average, physicians are waiting until the earliest born preterm infants are older before acid suppression therapy is prescribed. However, it is worrisome that 36.1% of preterm infants born on or before 26-weeks gestation that were ever treated with H2RAs, and 17.1% ever treated with PPIs, received their first dose within  the neonatal period (≤postnatal day 28). The neonatal period is a crucial time for intestinal microbiome development and acid suppression has been associated both with infection and necrotizing enterocolitis (NEC) in very low birth weight infants. We also found that the highest frequency of PPI treatment occurred in extremely preterm infants, as compared to later born preterm and term infants.

Our finding that the majority of infants ever started on an H2RA or PPI, and ∼75% of PPI users, remained on treatment at discharge was concerning to us because it might signify long-term acid suppression following discharge. Long-term use in adults has been associated with chronic renal disease and dementia in observational studies and we have no data on the long-term effects of persistent PPI or H2RA use in developing infants. What should clinicians and patients take away from your report?

Dr. Slaughter: Clinicians should take away the concern that despite limited evidence for the effectiveness of H2RA or PPI use in neonates and a lack of safety data, a large volume of the most fragile neonatal patients still receive H2RA/PPI treatment.  Clinicians must be careful to consider the potential negative effects of H2RA/PPI treatment in neonates and be cautious with their prescribing, especially given a lack of clear evidence for their effectiveness.

Parents and families of sick neonates should be sure to talk with their physicians about the benefits and risks of acid suppression treatment in their infants.  Although some sick infants with chronic health care needs and neurodevelopmental delay may eventually need long-term acid suppression as they grow older, most infants will outgrow reflux symptoms on their own as they grow.  When H2RA or PPI treatment is started, parents and caregivers should inquire about a plan for the length of treatment and when their infants might be potentially weaned off these drugs in the future. What recommendations do you have for future research as a result of this study?

Dr. Slaughter:  As expected, the highest probability of H2RA and/or PPI treatment occurred in infants with a GERD diagnosis. However, newborns with congenital heart disease had the next highest treatment probability with either drug (H2RA or PPI) and those with otorhinolaryngology (ENT) diagnoses had the second highest probability of receiving PPIs. Research on the use of acid suppression treatment on neonates with surgical and non-surgical ENT diagnoses is needed. Our study couldn’t confirm the reason for PPI treatment in infants with congenital heart disease, but peri-operative prophylaxis for stress ulcers seems a likely cause.  There is not much data on the effectiveness of stress ulcer prophylaxis in improving neonatal outcomes and that is a prime area for further research.

Randomized controlled trials where infants with symptoms (irritability, gagging, vomiting, coughing) potentially attributed to GERD were randomized to PPI treatment versus placebo showed no effectiveness in improving these symptoms despite a documented reduction in gastric acidity. However, there is a lack of randomized trials restricted to those infants with true, physiological diagnosed (via impedance probe) in addition to clinically symptoms. Such trials are needed.

Finally, large observational studies are needed to fully evaluate the long-term effects of neonatal medication exposures. Even the largest neonatal trials are limited to several thousand infants and are therefore not usually powered to detect important safety outcomes. Large, long-term and publicly available databases and cohort registries are needed to fully evaluate drug safety not only for H2RAs/PPIs, but for many other drugs commonly used in neonates.  We currently have few means of tracking neonatal drug exposures with longer-term child and adult outcomes. Thank you for your contribution to the community.


Jonathan L. Slaughter, MD, MPH, Michael R. Stenger, MD, Patricia B. Reagan, PhD, Sudarshan R. Jadcherla, MD. Neonatal histamine-2 receptor antagonist and proton pump inhibitor treatment at United States Children’s HospitalsThe Journal of Pediatrics, April 2016 DOI:10.1016/j.jpeds.2016.03.059

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on April 29, 2016 by Marie Benz MD FAAD