Reflux Medicines for Tiny Premature Babies: What Doctors Know, What They Don't, and How Care Is Changing

What two 2025 studies tell families about acid-reducing medicines in the NICU

Two new studies suggest that medicines meant to reduce stomach acid in premature babies have never been properly proven to help them, and that neonatal teams are already using them less often and for shorter periods. Doctors are still unsure whether these medicines are harmful, which is why many units now use them cautiously.

If your baby is in the neonatal intensive care unit (NICU), you may hear the word "reflux" many times. Babies spit up, arch their backs, fuss during feeds, or have pauses in breathing, and it is natural to wonder whether acid coming up from the stomach is the cause. This article explains what we know about reflux in premature babies and about the medicines often given for it, in plain language.

Why reflux is so common in premature babies, and why the medicines became popular

The two studies discussed here are a systematic review from the Cochrane group, which collects and weighs all of the best trials on a question [1], and a study of what doctors actually prescribed to more than 13,000 extremely premature babies in American NICUs [2].

Some reflux is simply part of being a newborn. The muscle that works like a valve at the top of the stomach is immature in premature babies, they spend a lot of time lying on their backs, they drink only liquid, and feeding tubes can hold the valve slightly open. Expert groups, including the American Academy of Pediatrics, have explained that this kind of reflux is normal and usually improves as babies grow, and that it is difficult to tell when it has become true reflux disease [3]. A careful review also found little proof that reflux causes the pauses in breathing and slow heart rates that often worry parents and nurses [4].

Because there is no simple test, doctors often decide that a baby has reflux disease based on how the baby looks and behaves. As a result, the diagnosis is made much more often in some hospitals than in others; in one study of 33 NICUs, the share of premature babies given this diagnosis ranged from about 2% to 30% [5]. In another large study of children's hospitals in the United States, about one in four babies who stayed in the NICU for more than a week received an acid-reducing medicine [6]. Research in slightly older infants with reflux symptoms, including a trial of one such medicine [7], has been described as showing that these medicines often do not ease symptoms.

The medicines in question come in two families. "Proton pump inhibitors" (PPIs) switch off the tiny pumps that make stomach acid, and "H2 blockers" lower acid in a different way. In adults with acid damage to the food pipe they are very helpful, so it seemed reasonable to try them in babies. But very few trials had been done in premature babies themselves. In the Cochrane review's search, only two small trials fitted: one that tested a PPI called omeprazole [8] and one that tested another, called esomeprazole [9]. An earlier review of acid-reducing medicines in premature babies had reached the same conclusion, that good studies were missing [10]. A study of infants who stayed on PPIs for weeks found that although their stomach acid exposure went down, the food pipe seemed to clear milk more slowly and symptoms did not improve [11].

There was also a safety worry. Several studies noticed that premature babies given acid-reducing medicines were more likely to develop a serious bowel illness called necrotizing enterocolitis, or serious infections [12],[13],[14]. These studies cannot prove the medicines caused the problems, because babies who are sicker are also more likely to be given medicines. Even so, the findings made doctors more cautious. Hospitals looked at how many babies were being sent home on reflux medicines [15], wrote guidelines to reduce their use [16], and ran quality-improvement projects to give them to fewer babies [17].

For families, this history has often meant living with uncertainty. A baby who arches at feeds or has an alarm sound on the monitor is hard to watch, and a medicine that promises relief is hard to refuse. Clinicians felt the same pull. For many years, giving an acid-reducing medicine was a way of doing something when the cause of a baby's discomfort was unclear, and because the medicines were available as liquids that could be given through a feeding tube, they were easy to start. What was missing was proof that they helped. Looking back, one older study of extremely small babies found that a notable share went home on reflux medicines [15], and later hospital projects set out specifically to reduce how often the medicines were used [16], [17]. That is the background against which the two new studies were done.

What the researchers did

The Cochrane team searched medical databases for trials of PPIs in premature babies with reflux disease or suspected reflux disease. They looked through more than 1,200 reports, read 27 in full, and found two trials that qualified, involving 62 babies in total [1]. In one, ten babies took the medicine for a week and a dummy medicine (placebo) for a week [8]. In the other, 52 babies received either the medicine or placebo for up to two weeks, and the study stopped early because too few families could be enrolled; it was paid for by the medicine's manufacturer [9].

The second study looked back at records of babies born at 22 to 27 weeks of pregnancy and discharged from NICUs in a large group of American hospitals between 2015 and 2020 [2]. The researchers counted how many received acid-reducing medicines, when treatment began, and how long it lasted.

What they found

The two trials could not show that the medicines helped. The babies who took esomeprazole had about the same number of breathing pauses, slow heart rates, dips in oxygen, choking spells and episodes of vomiting as the babies who took placebo, but the trial was so small that it could not rule out either a real benefit or a real harm [1]. The Cochrane authors rated this evidence as very uncertain. The medicines did reduce acid in the food pipe; in the small crossover trial, babies spent about 5% of the day with acid in the food pipe on omeprazole compared with about 19% on placebo [8]. That is a measurable effect on acid, but not proof the babies felt or did better.

In the large records study, about 11 out of every 100 extremely premature babies (1,489 of 13,735) received one of these medicines [2]. Most were started late in the hospital stay, around the time the baby reached the equivalent of a full-term pregnancy, and the typical course was about a week. Only about 3 in 100 were still taking them when they went home. Use dropped steadily over the five years, but it varied hugely between hospitals, from none of the babies at some to about three-quarters at others. More than half of the babies who got the medicines had no reflux diagnosis in their records. Babies who received the medicines were also more likely to have had infections, bowel illness and lung disease, but these babies were smaller and sicker to begin with, so this does not show that the medicines caused those problems.

What this means for your baby

The most honest message from these studies is "we don't yet know." There is no strong proof that acid-reducing medicines help premature babies with reflux, and no strong proof that they harm them, although the safety concerns are real enough that many teams prescribe them carefully [1],[2].

If your baby is offered one of these medicines, it is reasonable to ask a few questions. What symptoms is it meant to treat? Have feeding changes and positioning been tried? How long will it be given, and when will the team reassess? Most spitting up improves as babies mature, grow and move to bigger feeds, so patience and simple measures are often the first choice [3]. If your baby does receive a medicine, the studies suggest that short courses with a clear plan are the usual approach [2].

Families sometimes worry that choosing not to use a medicine means not treating their baby's reflux. The studies suggest otherwise: feeding and positioning changes, and giving time for the digestive system to mature, are the usual first steps, and the evidence does not show that adding a medicine reliably improves on them [3]. If you ever feel that your baby's symptoms are worsening, such as poor weight gain, repeated breathing pauses, or obvious distress with every feed, tell the team, because those signs deserve a proper assessment rather than an automatic prescription.

It can also help to know that fussiness, arching and spitting up are common in many babies and are not specific to reflux, which is a large part of why the diagnosis is so hard to make and why the medicines may not relieve these signs [3].

What researchers are working on next

Doctors want properly designed trials in premature babies, with enough infants to give clear answers about both benefit and safety [1]. They also want better ways to tell true reflux disease from the normal reflux seen in nearly every newborn. Researchers also hope to learn what happens after babies leave hospital, since the records study could not see whether babies were started on these medicines at home [2]. Until then, the most reassuring finding is that NICU teams are already being cautious, using these medicines less and for shorter times than in the past.

References

  1. King E, Horn D, Gluchowski N, O'Reilly D, Bruschettini M, Cooper C, et al. Safety and efficacy of proton pump inhibitors in preterm infants with gastroesophageal reflux disease. Cochrane Database Syst Rev. 2025;(3):CD015127. doi:10.1002/14651858.CD015127.pub2 ↩
  2. Lockyear C, Stark A, Foote HP, et al. Medical treatment of gastroesophageal reflux in the neonatal intensive care unit: current practice. J Perinatol. 2025;45(5):616-621. doi:10.1038/s41372-025-02238-9 ↩
  3. Eichenwald EC; Committee on Fetus and Newborn; Cummings JJ, et al. Diagnosis and management of gastroesophageal reflux in preterm infants. Pediatrics. 2018;142(1):e20181061. doi:10.1542/peds.2018-1061 ↩
  4. Poets CF. Gastroesophageal reflux: a critical review of its role in preterm infants. Pediatrics. 2004;113(2):e128-e132. doi:10.1542/peds.113.2.e128 ↩
  5. Jadcherla SR, Slaughter JL, Stenger MR, Klebanoff M, Kelleher K, Gardner W. Practice variance, prevalence, and economic burden of premature infants diagnosed with GERD. Hosp Pediatr. 2013;3(4):335-341. doi:10.1542/hpeds.2013-0036 ↩
  6. Slaughter JL, Stenger MR, Reagan PB, Jadcherla SR. Neonatal histamine-2 receptor antagonist and proton pump inhibitor treatment at United States children's hospitals. J Pediatr. 2016;174:63-70.e3. doi:10.1016/j.jpeds.2016.03.059 ↩
  7. Orenstein SR, Hassall E, Furmaga-Jablonska W, Atkinson S, Raanan M. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pediatr. 2009;154(4):514-520.e4. doi:10.1016/j.jpeds.2008.09.054 ↩
  8. Omari TI, Haslam RR, Lundborg P, Davidson GP. Effect of omeprazole on acid gastroesophageal reflux and gastric acidity in preterm infants with pathological acid reflux. J Pediatr Gastroenterol Nutr. 2007;44(1):41-44. doi:10.1097/01.mpg.0000252190.97545.07 ↩
  9. Davidson G, Wenzl TG, Thomson M, et al. Efficacy and safety of once-daily esomeprazole for the treatment of gastroesophageal reflux disease in neonatal patients. J Pediatr. 2013;163(3):692-698.e2. doi:10.1016/j.jpeds.2013.05.007 ↩
  10. Dermyshi E, Mackie C, Kigozi P, Schoonakker B, Dorling J. Antacid therapy for gastroesophageal reflux in preterm infants: a systematic review. BMJ Paediatr Open. 2018;2(1):e000287. doi:10.1136/bmjpo-2018-000287 ↩
  11. Sultana Z, Yildiz VO, Jadcherla SR. Characteristics of esophageal refluxate and symptoms in infants compared between pre-treatment and on treatment with proton pump inhibitors. J Perinatol. 2024;44(1):87-93. doi:10.1038/s41372-023-01825-y ↩
  12. Guillet R, Stoll BJ, Cotten CM, et al. Association of H2-blocker therapy and higher incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics. 2006;117(2):e137-e142. doi:10.1542/peds.2005-1543 ↩
  13. Terrin G, Passariello A, De Curtis M, et al. Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics. 2012;129(1):e40-e45. doi:10.1542/peds.2011-0796 ↩
  14. Athalye-Jape G, Rao S, Patole S, More K. Association of inhibitors of gastric acid secretion and higher incidence of necrotizing enterocolitis in preterm very low-birth-weight infants. Am J Perinatol. 2013;30(10):849-856. doi:10.1055/s-0033-1333671 ↩
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  16. Angelidou A, Bell K, Gupta M, Tropea Leeman K, Hansen A. Implementation of a guideline to decrease use of acid-suppressing medications in the NICU. Pediatrics. 2017;140(6):e20171715. doi:10.1542/peds.2017-1715 ↩
  17. Thai JD, Rostas SE, Erdei C, Manning SM, Angelidou A, Bell KA. A quality improvement initiative to reduce acid-suppressing medication exposure in the NICU. J Perinatol. 2022;42(8):1118-1125. doi:10.1038/s41372-021-01262-9 ↩