OBJECTIVES: To describe the epidemiology and management of gastroesophageal reflux (GER) medications started in the first year of life for premature infants.
METHODS: Retrospective review of a cohort of infants ≤35 weeks’ gestation presenting for care by 168 days of age to a 30-site network between 2005 and 2009 (n = 2217) and followed to 3 years of age. Medication frequency, types, and duration of use were assessed. Logistic regression identified factors associated with treatment.
RESULTS: Thirty-seven percent (812) were prescribed GER medications with 77% begun after NICU discharge. Ninety percent (727) received histamine-2 receptor antagonists, 33% (269) proton pump inhibitors, 22% (182) prokinetics; 40% (325) received >1 medication. Outpatient medication was initiated at 95 ± 69 days of life for total of 294 ± 249 days (interquartile ratio: 117–359). Feeding issues (adjusted odds ratio [aOR] 2.05, 95% confidence interval [CI]: 1.24–3.39) were associated with outpatient initiation. Forty-three percent (322) of infants started before 6 months were still on at 1 year of age associated with gestational age <32 weeks (aOR 1.76, 95% CI: 1.16–2.67), chronic lung disease (aOR 2.59, 95% CI: 1.29–5.22), and reactive airways disease (aOR 1.67, 95% CI: 1.05–2.65).
CONCLUSIONS: Of the 37% of the cohort on GER medications, 77% were started after NICU discharge with prolonged use of medications. Feeding difficulties were associated with starting medication and markers of chronic lung disease with continuation of treatment. With uncertain evidence of efficacy, use of these medications in a high-risk population should be carefully evaluated.
- ALTE —
- acute life-threatening event
- aOR —
- adjusted odds ratio
- CI —
- confidence interval
- ESPGHAN —
- The European Society for Pediatric Gastroenterology Hepatology and Nutrition
- GER —
- gastroesophageal reflux
- H2RAs —
- histamine-2 receptor antagonists
- IQR —
- interquartile ratio
- NASPGHAN —
- North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition
- PPI —
- proton-pump inhibitor
What’s Known on This Subject:
Premature infants are frequently diagnosed with gastroesophageal reflux. Efficacy and safety concerns have resulted in more judicious use of reflux medications in the NICU, although practice variation exists. Once started, many continue treatment at discharge.
What This Study Adds:
How these medications are managed after discharge is unknown. The majority of discharged premature infants receiving reflux medications were started on these in the ambulatory setting. Prolonged and concurrent use of medications was found.
Gastroesophageal reflux (GER) disease is a common diagnosis for premature infants in NICUs. Overall incidence of the disease has been reported to be ∼11.2%, but differences in rates of diagnosis have been reported.1–3 Consensus-based guidelines for the management of GER were developed in 1997 by the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) working group4 and in 2001 by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN).5 In 2009, ESPGHAN and NASPGHAN combined to publish guidelines6 that were endorsed by the American Academy of Pediatrics in 2013.7 According to the guidelines, the management of infants differs from that of older children in regard to the judicious use of medications, in part due to difficulties in diagnosis. The diagnosis of GER disease is often made clinically; regurgitation is common in infants, and symptoms such as irritability, distress, vomiting, and even weight loss are not specific to GER disease. These issues coupled with a lack of evidence for acid-related disorders in many infants alter the approach to a symptomatic infant.
Infants started on reflux medications in the NICU are frequently discharged from the hospital on these medications.3,8,9 Wade et al10 reported that 13% of the medications refilled for premature infants in the first year of life were reflux medications. However, concerns about the efficacy of these medications in infancy,6,7,11 which include a lack of symptomatic response to acid suppression in controlled studies12,13 and potentially serious complications such as necrotizing enterocolitis and bacteremia/sepsis,14,15 have led to more judicious use of GER medications in the NICU setting.16 Even with these guidelines and lack of efficacy, there remains wide variation in the use of medications to manage GER in NICUs among different health systems,2,3 within the same health system,17 between smaller and larger NICUs, and among different specialists involved in an infant’s care.18
There were no studies found regarding post-NICU management of reflux medication including duration of use, initiation of medication postdischarge, and factors associated with treatment. Thus, the purpose of this study was to describe the epidemiology and management of GER medications started during the first year of life for premature infants as documented in a primary care setting.
Setting and Study Population
A retrospective cohort design evaluated care received by preterm infants (defined by a gestational age of ≥22 and ≤35 weeks) in the primary care network at the Children’s Hospital of Philadelphia. Those born between January 1, 2005, and January 1, 2009, who presented for primary care by 168 days of life and seen at furthest to 3 years of life (1095 days) were included (N = 2316). The network included 30 urban and suburban sites in Pennsylvania and New Jersey. Infants with syndromes, congenital anomalies, and disorders of the gastrointestinal tract and perinatal asphyxia were excluded (n = 99; see Supplemental Table 4). The remaining 2217 (95.7%) met eligibility criteria.
This study was approved by the Children’s Hospital of Philadelphia Institutional Review Board. Patient information was documented by providers during ambulatory health care encounters in the electronic record using the EPIC Hyperspace system (Verona, WI).
Determination of GER Medication Use
The electronic record was searched for all infants with the diagnosis of GER using International Classification of Diseases, Ninth Revision, codes 530.11, 530.10, 530.12, 530.81, and 787.1. The ambulatory medication record was searched for reflux medications using both generic and trade names regardless of GER diagnosis. In addition, a text search of all ambulatory notes in the first year of life was performed to capture prescription of medications by subspecialists that were not included in the ambulatory medication record. Searched medications included histamine-2 receptor antagonists (H2RAs): ranitidine (Zantac); nizatidine (Axid), famotidine (Pepcid); proton pump inhibitors (PPIs): esomeprazole (Nexium), omeprazole (Prilosec), lansoprazole (Prevacid), pantoprazole (Protonix); prokinetic: metoclopramide (Reglan); and cholinergic: bethanechol (Urecholine).
Medication stops and starts were hand-coded and reconciled with the medication file. If a discrepancy was found, the information hand-coded from provider notes was used because of concerns about the accuracy of medication file reconciliation. If start or stop dates were unclear, the dates were interpolated to the midpoint between visits when the medication was last noted to be used and first noted to be discontinued (median 19 days after previous visit, interquartile ratio [IQR] 9–35 days). Duration of treatment was assessed until 3 years (1095 days) of age.
Because the first notation in the ambulatory medication record might reflect a refill of NICU medication, records from the initial presentation to the primary care site, along with any NICU discharge information provided to the outpatient provider, were reviewed manually to ensure this was a preexisting medication and not one that was started initially at the first visit.
Confounding Variable Definitions
Demographic factors included gestational age, birth weight, ethnicity, race, sex, and multiple gestation, as well as site of primary care. Insurance type was divided into 3 exclusive categories: any office visit without insurance; any use of federal Medicaid insurance without ever being uninsured; and sole use of private insurance during the study period. Potential confounding medical factors as noted in the ambulatory setting during the first year of life included chronic lung disease, reactive airways disease, failure to thrive, aspiration, airway malacia, feeding difficulties, dysphagia, fundoplication, acute life-threating event (ALTE)/apnea, the need for tube feedings, and supplemental oxygen (see Supplemental Table 5).
Descriptive analysis included cohort demographics, frequencies of medications, chronological and adjusted age at medication initiation, duration of use, use of >1 reflux medication, and simultaneous use of >1 medication. Univariate analysis included χ2 analysis and binary logistic regression identifying factors associated with medication initiation in the outpatient setting, duration of use, and the use of >1 medication. A multivariate logistic regression model quantified the association of the marginal impact of these factors on the likelihood that a medication was ever prescribed; multiple medications were prescribed; and the likelihood that a child received medications at 6 months and 1 year chronological age. As a secondary analysis, the model was repeated using 6 months and 1 year of age after adjusting for gestational age at birth. These models used random effects for outpatient clinical site to control for clustering of outcomes and use by site. Because few infants in this cohort had a fundoplication, this variable was not included in the regression models. A Cox proportional hazards model assessed factors associated with duration of treatment using fixed practice effects to control for differences in duration of treatment by outpatient site.
Overall, 37% (812) of the infants in the cohort were on GER medications during the first year of life. Of these 185 (23%) were started in the NICU, with the remainder (627; 77%), started after presentation to the ambulatory network (Table 1). Infants who were treated tended to be of lower gestational age (P < .0001), white (P < .0001), privately insured (P = .003), be of multiple gestation (P < .0001), and had more medical complications (Table 1). Nearly all received H2RAs, 90% (727), followed by PPIs 33% (269), prokinetics 22% (182), and cholinergics 2% (18).
Start and stop dates were available for 66% of the cohort and interpolated for the remainder. Ambulatory GER medication was started at mean chronological age 95 ± 69 days (median 73; IQR 46–124); and mean adjusted age of 44 +/−62 days (median 21; IQR 0-56), adjusting for prematurity.
Multiplicity of Medications
More than one-third of the treated infants, 40% (325), were on >1 GER medication during the first year of life. Of those, the majority, 73% (238), were on those medications simultaneously, with 61% (197) on 2, 11% (37) on 3, and 1% (4) on 4 medications at the same time. Simultaneous treatment with a H2RA and PPI was found in 30% (99) of those treated with >1 medication with simultaneous use averaging 118 ± 146 days (median 61; IQR 20–182). Simultaneous use of 3 acid-blocking medications was found in 3% (11) of infants averaging 87 ± 93 days (median 32; IQR 11–136).
Feeding issues (adjusted odds ratio [aOR] 2.05, 95% confidence interval [CI] 1.24–3.39) were associated with the start of medication in the outpatient setting (Table 2). Dysphagia, ALTE/apnea, and lower gestational age were associated with a decreased likelihood of being started on GER medication in the outpatient setting. Practice site accounted for 6.2% (95% CI: 1.6–20.6) of the residual variation in the likelihood of receiving a medication as an outpatient after adjusting for the covariates shown in Table 2.
We found a strong association with lower gestational age and how GER medications were managed in the ambulatory setting. Factors associated with receipt of >1 GER medication included gestational age <32 weeks (aOR 2.36, 95% CI: 1.59–3.52); feeding difficulties (aOR 1.46, 95% CI: 1.03–2.06), tube feeding (aOR 4.56, 95% CI: 1.09–19.1), need for supplemental oxygen (aOR 2.63, 95% CI: 1.07–6.44), and asthma (aOR 1.64, 95% CI: 1.08–2.49) (Table 2).
Duration of Use
We found prolonged use of medication. For those on medication at NICU discharge, mean duration of use was 375 ± 292 days (median 284, IQR 165–515). For those started after NICU discharge, mean duration of use was 294 ± 249 days (median 225, IQR 117–359). For infants started on GER medication before 6 months of age (743 infants), gestational age <32 weeks (aOR 2.16, 95% CI 1.26–3.71) and reactive airways disease (aOR 2.17, 95% CI: 1.09-4.3) were associated with continued medication use at 6 months’ chronological age (Table 3). There were 69 infants who started initial treatment after 6 months of age.
By chronological age of 1 year, 43% (322) of the infants started on medication before 6 months were still being treated. Factors associated with a higher likelihood of medication at chronological age of 1 year included gestational age <32 weeks (aOR 1.76, 95% CI: 1.16–2.67); chronic lung disease (aOR 2.59, 95% CI: 1.29–5.22), airway malacia (aOR 2.79, 95% CI: 1.24–6.3), and reactive airways disease (aOR 1.67, 95% CI: 1.05–2.65) (Table 3). Those with any use of Medicaid insurance were less likely to be on medication at 1 year (aOR 0.62, 95% CI: 0.39–0.97). As a sensitivity analysis, we reran the models looking at continued use at 6 months and adjusted age of 1 year. Overall, the adjusted age models confirmed the chronological age models with the lowest gestational age infants and those with markers of lung disease continuing to receive treatment at 1 year. In addition, failure to thrive was a predictor for continued use at 1 year of adjusted age. Reactive airways disease was not a significant predictor using adjusted age, and multiple-gestation infants were less likely to be on medication at 1 year of adjusted age (see Supplemental Table 6).
Gestational age <32 weeks was associated with a 31% longer use of GER medications (hazard ratio 0.69; 95% CI 0.57–0.84), and a gestational age of <28 weeks was associated with a 50% longer use (hazard ratio 0.50; 95% CI 0.38–0.66) compared with a gestational age of 34 to 35 weeks (Table 3). Of the treated infants, 92 were lost to follow-up between 18 and 36 months. By 3 years of age, 4% (32) of the children were still being treated (Fig 1).
Most literature regarding the management of GER for premature infants has focused on the NICU setting. To our knowledge, this is the first study to explore the outpatient management of GER medications for premature infants who were started during the first year of life. We found that close to 40% of our cohort received reflux medications. Previous reports of the prevalence of GER disease in premature infants have been derived from the NICU setting.1–3 The inclusion of what happens after discharge reveals a greater scope of this issue for premature infants. We found that more than three-quarters of the premature infants on reflux medications in the ambulatory setting were not on these medications at NICU discharge but instead were started on medication after discharge with modest variation between outpatient sites. Although there is increasing awareness of the need for judicious use of these medications in the NICU setting,16 we found frequent use of these medications for premature infants in the outpatient setting.
The efficacy of reflux medications in the management of GER disease in infants has been questioned.6,7,11,19 Although there remains a role for these medications in documented reflux disease, empirical treatment of infants is not recommended.6,7 In addition, adverse outcomes such as community-acquired pneumonia,20–22 gastroenteritis,21,23 lower respiratory tract infections,12 Clostridium difficile infection,24,25 alterations in lung microflora,26 and fractures27,28 have been reported with the use of acid-blocking medications.
H2RAs were the most commonly prescribed medication in our study. A recent systematic review found that, because of the low quality of available evidence, conclusions regarding the safety and efficacy of H2RAs for infants could not be determined, and H2RAs should be used cautiously and only with acid-confirmed reflux disease.29 Rapid tachyphylaxis with H2RAs has been reported starting as early as second day/second dose.30 The associated costs and value of using these medications with questionable efficacy have significant health services implications.
PPIs have not been shown to be effective for those <1 year of age in the management of GER disease symptoms.12,13,31–33 However, we found frequent use of PPIs in our cohort with 22% (180) of those treated with a reflux medication receiving a PPI. These findings are similar to information from US retail pharmacies, which in 2010 found that PPIs were a top drug dispensed to children from US retail pharmacies.34 Although guidelines suggest consideration of a short-term time-limited trial of medication if other measures fail,6,7 once these medications were started, we found that infants tended to stay on medication for prolonged periods of time, possibly influenced by lung disease and reactive airways, which were predictors for prolonged use of medication. We also found that 40% of the treated infants received >1 reflux medication, with the majority of those infants concurrently receiving ≥2 medications, along with prolonged concurrent use of H2RAs and PPIs. Because premature infants are a medically fragile group, the need for 1 acid-suppression medication, let alone ≥2 in combination, should be given careful consideration. The potential impact of acid suppression on community-acquired illnesses has yet to be explored for this vulnerable population.
In our study, infants were started on medication at a mean chronological age of 3 ± 2 months of age. We found feeding issues to be a predictor for outpatient initiation of medication. Physiologic reflux symptoms are reported to peak at 4 months of age.35 Feeding issues are also common for premature infants.36 Whether this combination of issues is influencing the decision to start treatment, as opposed to actual GER disease, is an important distinction for providers to consider before starting medication. There is a lack of controlled data confirming reflux as the cause of these issues.6 Those with dysphagia, ALTE/apnea, and lower gestational age were less likely to initiate treatment in the outpatient setting, which most likely reflects these infants being started on treatment in the NICU setting.
There were small differences in the likelihood of receiving a GER medication between outpatient providers after controlling for patient-level factors. This degree of variation, however, was not large compared with other medications without strong indications for prescription. An issue that may affect management is that premature infants are frequently followed by specialists in addition to their primary care provider. This multiplicity of providers potentially complicates management and may influence the duration of treatment as ownership of reflux medication management may be unclear.
Although the NASPGHAN/ESPGHAN management guidelines have existed for many years, European studies have found that the majority of surveyed general pediatricians had limited awareness of the guidelines that promote conservative treatment.37,38 Conservative management has been shown to be an effective means to avoid medication for some infants.6,39–41 In 1 study, conservative therapy measures taught in a primary care setting, including feeding modifications, positioning, and tobacco smoke avoidance, resulted in symptom improvement in 78% of the infants with resolution of symptoms in 24%.40 The introduction of a training for European primary care physicians was found to increase compliance to guidelines and significantly decreased prescription of medication.37 Guidelines published by the American Academy of Pediatrics provide decision trees regarding the approach to infants with GER symptoms. Conservative management, parental education, assurance, and the avoidance of medication and additional testing for infants with uncomplicated regurgitation is recommended. However, symptoms of reflux accompanied by weight loss are indicators that further investigation and alteration in clinical management is warranted.7
Limitations for our study included actual stop and start dates not being clearly documented for approximately a third of the dates, thus necessitating interpolation. Because the midpoint between known dates off and on medication was used and the median interpolation was 19 days, this should not have significantly affected our results. The duration of treatment may be an underestimate because a few children were still receiving medication at the conclusion of the 3-year study period. These children may not reflect the experience of the vast majority of infants who stopped medications by 3 years of age. Information regarding diagnostic workup for GER disease was not retrievable for the entire cohort, limiting the ability to determine if treatment was initiated based on clinical opinion or diagnostic evaluation.
A lack of evidence supporting the efficacy and safety of reflux medications has led to changes in neonatal practice. Until now, how these medications were being managed in the ambulatory setting after NICU discharge was unknown. Of the 37% of the premature infants in our cohort on GER medications, 77% were started after NICU discharge with a median duration of 294 days. Feeding difficulties were associated with starting medication and markers of chronic lung with continuation of treatment. With uncertain evidence of efficacy, the rationale for using these medications in this high-risk population should be carefully evaluated.
- Accepted September 13, 2016.
- Address correspondence to Scott A. Lorch, MD, MSCE, Center for Outcomes Research, The Children’s Hospital of Philadelphia, 3535 Market St, Suite 1029, Philadelphia, PA 19104. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: All phases of this study were supported by National Institutes of Health grant R01 HD057168. Funded by the National Institutes of Health (NIH).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2016-2849.
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- Copyright © 2016 by the American Academy of Pediatrics