PPIs are often prescribed to infants and children to treat of GERD.

Studies based on pH-metry/resistance measurements have shown that PPI administration can reduce the reflux of acidic gastric contents, but not the total number of reflux episodes percentage of time that gastric contents remain in the esophagus, or GERD [13]. Consequently, while PPIs appear to effectively treat of reflux esophagitis, they do not treat extraesophageal manifestations of GERD as effectively as they treat manifestations of the respiratory system [14,15]. Both clinical manifestations and mucosal damage recur in a significant number of patients after PPI discontinuation or dose reduction [16].

According to the latest guidelines updated 2018 of the ESPGHAN/NASPGHAN (European and North American Society of Pediatric Gastroenterology, Hepatology and Nutrition) for GERD, PPI use is restricted to children with typical clinical manifestations, but not those with extraesophageal manifestations (asthma, chronic cough, laryngitis, hoarseness, chronic pharyngitis, dental erosion and retrosternal pain of noncardiac etiology), except in the presence of typical GERD symptoms or in otherwise healthy infants with anxiety or visible reflux; however they are a first-line treatment for corrosive gastritis due to chronic exposure of the esophageal mucosa to acidic gastric fluids [17].

The term “peptic ulcer” refers to an erosion site on the inner wall of the stomach (gastric ulcer) or the first portion of the small intestine (duodenal ulcer). Helicobacter pylori infection, the ingestion of pharmaceutical preparations such as nonsteroidal, anti-inflammatory drugs, various systemic diseases, and stressful situations (multiorgan failure, burns, shock and major surgery) are predisposing conditions that pathogenetically influence the occurrence of a peptic ulcers. However, in many cases the primary cause of the ulcer development remains unknown.18) Clinical experience has shown that the administration of even low doses of PPIs (0.3–0.7 mg/kg/day) can contribute to ulcer healing [18].

Zollinger-Ellison syndrome and G-cell hyperplasia of the gastric cavity are extremely rare disorders in the pediatric population characterized by the hypersecretion of gastric acid leading to the formation of gastroduodenal ulcers, which often recur. To control gastric acid secretion and its complications, the administration of PPI at high doses (≥ 80 mg/24 hours) is recommended [18].

PPIs are part of the treatment to eradicate Helicobacter pylori according to 2024 ESPGHAN guidelines [19]. The goal of treatment is to achieve 90% eradication. However, this is not always possible due to the development of antibiotic resistance in these strains, as well as limited patient compliance.

PPIs can be administered to treat pain in functional digestive disorders [20]. They are reportedly to be more effective than H2 blockers at relieving pain [21].

PPIs are sometimes prescribed to children to manage drug-induced dyspepsia, particularly when epigastric pain or reflux symptoms are prominent. However, their routine prophylactic use is not supported by strong evidence; thus, PPIs should generally be reserved for children at higher risk, such as those with a history of ulcer disease or significant comorbidities. The shortest effective duration, should be employed because PPIs can alter the gut microbiota and potentially worsen complications when combined with nonsteroidal anti-inflammatory drugs or corticosteroids [22].

EoE is a chronic, local, immune-mediated disease characterized by dense eosinophilic infiltration of the esophageal mucosa with symptoms of esophageal dysfunction. Its prevalence and frequency have increased significantly in recent decades. EoE is the most common cause of dysphagia and lumpiness in children and significantly impairs their quality of life [2]. PPIs are used to achieve clinical response and histological remission in patients with EoE [23], especially those with signs of increased gastric acid secretion.

The recent 2024 update of the 2014 [24] ESPGHAN guidelines on EoE recommend the use of PPIs for the induction of remission of EoE as one of 3 treatment strategies (PPIs, elimination diet or topical steroids) and not as a diagnostic criterion [22]. In patients who respond to PPIs, long-term treatment with these therapeutic agents is recommended, as symptoms and esophageal eosinophilia usually recur within 3–6 months after discontinuation of treatment [22]. However, PPI duration and dose for maintenance therapy have not yet been established. In the absence of new data in literature, it seems reasonable to gradually reduce the administered dose to the lowest possible required to maintain remission [22].

The recommended treatment regimens for PPI dosage and duration of administration are listed in Table 1.

PPIs are metabolized by the hepatic cytochrome P450 enzyme system, with the isoenzymes CYP2C19, CYP3A4, and CYP1A playing an essential role. These enzymes play important roles in the metabolism of other substances and drugs such as warfarin, diazepam, clopidogrel, theophylline, phenytoin, and methotrexate. This common metabolic pathway may lead to drug interactions and alter their pharmacokinetics and pharmacodynamics; therefore, special care must be taken when administering these drugs simultaneously [25].

Evidence is limited for the use of PPIs by preterm infants with GERD. Small trials indicated that PPIs reduce gastric acid but do not clearly improve symptoms or cardiorespiratory events, and no studies have compared PPIs with nonpharmacologic measures such as positioning or dietary changes; safety data are also insufficient, so routine use is not supported [6]. An observational analysis of 464 adverse events reported to the U.S. Food and Drug Administration that occurred in reports in neonates and infants receiving PPI monotherapy found that 69.6% of the events were serious—including vomiting, diarrhea, hypertrichosis, choking, and erythema—with vomiting being the most frequent (reporting odds ratio, 2.88); 3.2% were temporally related to mortality, and 10.8% involved medication errors, highlighting substantial safety concerns and the need for improved neonatal pharmacovigilance [26]. A multicountry observational study of infants in Denmark, Norway, and Sweden (2007–2020) reported a more than fourfold increase in PPI dispensing despite guideline recommendations against their routine use in infancy; in 2020, the dispensing rates were 46.4, 23.4, and 18.9 per 1,000 infants per year in Denmark, Norway, and Sweden, respectively, suggesting widespread and likely unnecessary PPI use with significant variation across countries [27].

The most common side effects of (prolonged) PPI use are shown in Table 2.

PPIs are among the most commonly prescribed medications in infants and children, and their use has increased in recent decades despite limited evidence of their efficacy [28]. Their long-term use has been associated with disorders that we explore below. Common side effects, occurring in 1%–3% of patients, include: headache, nausea, rash, dizziness, diarrhea or constipation, flatulence and epigastric discomfort. However, in addition to the usual immediate side effects, prolonged use of these drugs is also of concern, as the prolonged inhibition of gastric acid production is associated with persistent hypergastrinemia and hyperplasia of enterochromaffin-like (ECL) cells, leading to the development of gastric polyps, atrophic gastritis, cancer, vitamin B₁₂ deficiency, hypomagnesemia, osteoporosis and bone fractures; disruption of the gastrointestinal microbiome; and an increased risk of infection, necrotizing enterocolitis, kidney damage, and other conditions [29,30]. The potential side effects of PPIs are shown in Fig. 3 [30].

Due to the antisecretory effect of PPIs, changes in physiological balance with their use lead to gastrin hypersecretion. Gastrin stimulates cell proliferation. In addition, increased levels of chromatographin A lead to chronic stimulation of ECL cells [31]. In recent years, an increase in adenoid polyps of the gastric fundus has been observed after long-term PPI use [32]. These polyps are usually benign, multiple and located in the mucosa of the gastric vault and body; however, dysplastic disorders have also been described in some cases [33].

There is some evidence that long-term PPI use in adults may be associated with an increased risk of developing precancerous lesions such as polyps, mucosal atrophy, metaplasia and gastric cancer [33,34]. Gastrin is a hormone produced by G cells in the pyloric antrum of the stomach. Gastrin induces gastric acid secretion by binding to cholecystokinin 2 receptors on the enterochromaffin cells of the dome and body and simultaneously releasing histamine, which in turn stimulates the parietal cells of the stomach to secrete hydrogen ions. Moreover, gastrin regulates processes such as cellular proliferation, apoptosis, infiltration and angiogenesis and is suspected to play a role in gastric cancer developement [35]. Long-term PPI use is associated with gastrin hypersecretion; therefore, prolonged use should be evidence-based and regularly reassessed, especially in children and adolescents [36].

Vitamin B₁₂ is involved in the metabolism of all human cell types. It is particularly important to normal functioning of the nervous system because of its role in the myelin synthesis and red blood cell maturation in the bone marrow. Vitamin B₁₂ deficiency is usually caused by insufficient intake but can also be caused by malabsorption, intestinal diseases, low binding protein levels and the use of certain medications. PPIs inhibit the production of hydrochloric acid by the parietal cells of the stomach, which converts pepsinogen to pepsin. Pepsin aids the release of B₁₂ from food. The absence or deficiency of gastric acid reduces pepsin levels, resulting in reduced B₁₂ release and reduced availability for its absorption in the ileum [20]. Reduced B₁₂ administration was observed in empirical studies following PPI use. Other studies have shown that, after several months of PPI use in adults, significantly reduced absorption of protein-bound vitamin B12 but unaffected absorption of unbound B₁₂ [37].

Recent studies reported that PPI use may be an independent risk factor for osteoporosis and bone fractures [38]. The presence of hypochlorhydria, which occurs with PPI use, can reduce calcium solubility, resulting in reduced intestinal absorption and a negative calcium balance. Data from different studies are contradictory, as some have shown that PPI use is associated with reduced calcium absorption, while others have not [39].

Long-term PPI use is associated with the occurrence of hypomagnesemia. Mg absorption occurs via a passive and active transport mechanism involving 2 proteins (transient receptor potential melastatin 6 and 7), in the apical membrane of enterocytes, which have a high affinity for Mg absorption and ensure its balance during times of its reduced intake. The activity of these proteins is influenced by their intraluminal acid–base state. An acidic environment increases their activity, whereas PPI ingestion decreases it, leading to reduced Mg absorption and hypomagnesemia, as shown in several studies and case reports. A recent meta-analysis [40] showed that the long-term use of PPIs, especially when administered at high doses, is associated with an increased risk of hypomagnesemia. The authors concluded that Mg levels should be monitored in patients taking high doses of or long-term of PPIs.

The risk of fractures in the general population taking PPIs has been investigated in several studies [41] and meta-analyses [42], and an increased risk of fractures has been reported in patients taking PPIs, independent of other complicating factors. One study [38], of children aged 4–17 years followed up over a 5-year period reported, a positive association between PPIs and an increased risk of fracture.

However, in a recent retrospective cohort study [43] involving 851,631 children, 97,286 (11%) of them were prescribed acid-suppressive therapy in their first year of life: 7,998 (0.9%) received PPIs, 71,578 (8%) H2RAs and 17,710 (2%) a combination of PPIs and H2RAs. Children with other medical conditions associated with an increased risk of fractures were excluded from the study. The authors reported that children who received acid-suppressive therapy in infancy suffered fractures earlier in life (3.9 years vs. 4.5 years). They also found that an increased risk of fracture was associated with the use of PPIs (21%) or combined PPIs and H2RAs (30%), but not when H2RAs were used alone. Longer treatment duration and earlier age at treatment initiation were associated with an increased risk of fracture. Hypergastrinemia and decreased acid secretion are possible mechanisms underlying the association between PPIs and occurrence. As mentioned above, long-term PPI use increases gastrin levels. Elevated gastrin levels appear to cause secondary hyperparathyroidism, which negatively affects bone remodeling. Moreover, hypergastrinemia causes enterochromaffin cells hyperplasia and histamine hypersecretion. Increased histamine secretion may increase the differentiation of osteoclast precursors, although its effect on the bone is not entirely clear. The reduced acid secretion observed with PPI use leads to reduced absorption of trace elements such as Ca and Mg, which are involved in bone metabolism. The reduced vitamin B12 content and a vitamin B₆ and folic acid deficiencies observed with long-term PPI use lead to hyperhomocysteinaemia, which negatively affects bone and collagen quality. Vitamin B deficiency can lead to neurological disorders and muscle weakness, which also contribute to the occurrence of bone fractures [41].

Almost all parts of the human body have their own microbiome. Microbiome composition is determined by environmental and intramicrobial factors [44]. PPIs are used to suppress gastric acid. However, their long-term use has been associated with changes in the acidity of gastric juices, potentially affecting the microbiome of the stomach and intestine an individual's overall health. Studies have shown that PPI use is associated with dysbiosis, microbial overgrowth in the small intestine and changes in the microbiota composition [45,46], in terms microorganism types and diversity [44]. In patients taking PPIs, significant increases in Streptococcaceae and Enterococcaceae and decreased Faecalibacterium loads were noted [45], in other studies [44], PPI use led to species diversification and increased species in the microbiota of the upper respiratory tract and oral cavity. PPIs can alter the normal microbiota throughout the gastrointestinal tract. In the esophagus, they modify the physiological environment, leading to reduced exposure of the lower esophagus to gram-negative bacteria, which may reduce an individual's risk of developing Barrett esophagus. In the stomach, they alter microbial population and species such as H. pylori that have implications for peptic ulcers and stomach cancer. They also cause microbial overgrowth in the small intestine, which is associated with the occurrence of coeliac disease. In the large intestine, PPI use has been associated with Clostridium difficile infection, possibly through changes in the anaerobic microbiota in the large intestine [47].

A nationwide French cohort study of over 1.2 million children found that PPI use in early childhood was associated with an increased risk of serious infections. Children exposed to PPIs had a higher risk of infections overall (adjusted hazard ratio, 1.34) as well as at specific sites, including the digestive tract, respiratory tract, ear/nose/throat, urinary tract, and nervous system. Bacterial and viral infections were also more frequent among PPI users. These findings suggest that PPIs may compromise immune defenses or alter the microbiota, highlighting the need for their cautious use in young children [48].

Over the last 2 decades, C. difficile infection rates have increased worldwide, both frequency and severity. A meta-analysis [49], of 46 studies (40 case-control studies, 16 cohort studies) with 356,863 patients showed that, despite the limitation that these were observational studies and a causal relationship could not be proven, PPI use increases the likelihood of C. difficile infection by almost twofold. Another recent meta-analysis [50], which also included pediatric patients, found a strong association between PPI use and the occurrence and recurrence of C. difficile infection.

PPI use has also been associated with the occurrence of microbial gastroenteritis in pediatric patients [51]. PPI induced gastric acid suppression leads to the loss of their antimicrobial properties against microbes, i.e. pathogens that cause gastroenteritis.

Studies in adults have shown an increased association between PPIs and community-acquired pneumonia. In a multicenter study [51], in Italy, children with GERD aged 4–36 months were treated with PPIs and H2 agonists and developed community-acquired pneumonia more frequently than the healthy controls. Another study showed that PPI treatment was associated with more frequent lower respiratory tract infections in infants aged 1–12 months [52].

The use of gastric acid-inhibiting drugs such as PPIs and H2RA in patients within the neonatal intensive care unit is associated with a higher incidence of necrotizing enterocolitis and more frequent episodes of microbiome/alterations and sepsis [53]. Particular caution should be exercised, when administering these drugs to preterm or term infants [53].

PPI use has also been reported to be associated with renal injury such as acute renal failure, acute interstitial nephritis, chronic renal impairment and chronic renal failure, although there are currently no studies in pediatric patients [54]. Acute kidney injury is considered immunemediated, and affects interstitial tissue and renal tubules. The epithelial cells of the tubules are damaged first, followed by lymphocytic inflammatory infiltration. This can lead to renal scarring and decreased renal function [54]. In a cohort study, chronic PPI use was associated with an increased risk of chronic kidney damage. Similar results were found in another large cohort study in which PPI use was associated with an increased risk of renal dysfunction and chronic renal failure [54,55].

Long-term PPI use in adults may be associated with an increased risk of cardiovascular disease, stroke, and myocardial infarction [56]. Several mechanisms have been hypothesized, such as deficiency of the trace elements Mg and Ca, of vitamins, their effect on enzymatic metabolic pathways, and interactions with drugs, such as clopidogrel, whose antiplatelet effect is reduced by PPIs. It has been suggested that their long-term intake may reduce nitric oxide synthase activity, leading to the dysregulation of vascular homeostasis. They have also been shown to impair endothelial lysosomal acidification in vitro, disrupt the protease system and accelerate vascular aging [56]. Therefore, their limited use is recommended with consideration of all possible risks, and the duration of administration should be regularly re-evaluated [56].

There have been reports of children developing hirsutism after taking omeprazole [57]. Omeprazole significantly increases prostaglandin E2 synthesis in the duodenum. Prostaglandins appear to be involved in the regulaion of hair growth; E2 and F2α, stimulate it, whereas D2, inhibits it.