Eneonatal review newsletter, volume 10, issue 7

eNeonatal Review VOLUME 10, ISSUE 7
TREATMENT STRATEGIES FOR GERD IN NEONATES
In this Issue.
Length of Activity
Gastroesophageal reflux (GER), the passage of gastric contents into the esophagus, is 1.0 hour Physicians common in neonates and infants. Regurgitation with clinical y significant sequelae 1.0 contact hour Nurses constitutes a diagnosis of gastroesophageal reflux disease (GERD). Five current studies Launch Date
reviewed in this issue continue to support recommendations for nonpharmacologic treatment. Corvaglia, et al, Lasekan, et al, and Indrio, et al showed potential benefit fromextensively hydrolyzed protein formula, low-lactose rice-thickened formula, and probiotic treatment, respectively. Davidson, et al and Hussain, et al continue to show no benefit to proton pump inhibitor (PPI) treatment of GERD with validated measures of GERD signsand symptoms. The sixth study, by Barnhart, et al, showed no benefit from prophylacticfundoplication to prevent GERD sequelae in high-risk neurological y impaired infants. This TO ACCESS A
review wil demonstrate the value of nonpharmacologic and nonsurgical treatment of GERD in neonates and infants.
Review the CE Information LEARNING OBJECTIVES and study the educational After participating in this activity, the participant will demonstrate the ability to:
Select a post-test link at the end of the newsletter.
Explain the impact of the distinction between gastroesophageal reflux andgastroesophageal reflux disease on interpretation of study end-points.
Fol ow the instructions to Describe current evidence supporting nonpharmacologic vs pharmacologic treatment access a post-test.
options for GERD in neonates and infants.
Summarize the role of the natural history of GERD symptoms on symptomatic Please see the link at the improvement in GERD treatment and GERD research.
end of this newsletter to confirm your state's The Johns Hopkins University School of Medicine takes responsibility for the
acceptance of CE Credits.
content, quality, and scientific integrity of this CME activity.
PLANNER DISCLOSURES
Program Begins Below
As a provider approved by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy Lawrence M. Nogee, MD discloses that he has
served as a contributor to UpToDate, Inc.
of the Johns Hopkins University School of Medicine Office of Continuing Medical Education (OCME) to require signed disclosure of the existence of financial No other planners have indicated that they have any relationships with industry from any individual in a financial interest or relationships with a commercial position to control the content of a CME activity entity whose products or services are relevant to the sponsored by OCME. Members of the Planning content of their presentations.
Committee are required to disclose al relationships regardless of their relevance to the content of the Note: Grants to investigators at The Johns Hopkins activity. Faculty are required to disclose only those University are negotiated and administered by the relationships that are relevant to their specific institution which receives the grants, typical y through presentation. The fol owing relationship has been the Office of Research Administration. Individual reported for this activity: investigators who participate in the sponsored

project(s) are not directly compensated by the sponsor, but may receive salary or other support from the institution to support their effort on the project(s). GUEST AUTHORS OF THE MONTH Commentary & Reviews Guest Faculty Disclosure
Anna Maria Hibbs, MD, MSCE,
FAAP
The authors have indicated that Associate Professor of Pediatrics they have no financial interests University Hospitals Rainbow or relationships with a Babies & Children's Hospital commercial entity whose products or services arerelevant to the content of theirpresentation. Margaret Kuper-Sassé, MD
The authors have indicated that Neonatal-Perinatal Medicine Fel ow there wil be references to University Hospitals Rainbow proton pump inhibitors and Babies & Children's Hospital Program Directors Maureen Gilmore, MD
Assistant Professor of Pediatrics
Director of Neonatology Johns Hopkins Bayview Medical Center Baltimore, Maryland Edward E. Lawson, MD
Professor of Pediatrics Chief, Division of Department of Johns Hopkins Children's Center Baltimore, Maryland Lawrence M. Nogee, MD
Department of Pediatrics – Neonatology Johns Hopkins University School of Baltimore, Maryland Mary Terhaar, DNSc, RN
Associate Professor Director, DNP Program Johns Hopkins University School of Baltimore, Maryland

Anthony Bilenki, MA, RRT
Director Respiratory Care/ECMO The Johns Hopkins Hospital Baltimore, Maryland Gastroesophageal reflux (GER), the passage of gastric contents into the esophagus, iscommon and normal in neonates and infants. Regurgitation with clinical y significantsequelae constitutes a diagnosis of gastroesophageal reflux disease (GERD). Therefore, itis essential that trials of therapies for GERD assess GERD-defining symptoms, not onlyphysiologic measures of GER. The North American Society for Pediatric Gastroenterology,Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology,Hepatology, and Nutrition jointly recommend nonpharmacologic treatment approaches forGERD in neonates.1 The six studies reviewed in this newsletter continue to support earlierliterature recommending conservative nonpharmacologic interventions.
Three recent studies examine potential strategies for nonpharmacologic treatment in theseinfants. Corvaglia, et al. investigated the effect of extensively hydrolyzed protein formula toreduce GER in preterm infants. This pilot study in preterm infants used multichannelintraluminal impedance (MII) with pH probe to show a reduction in gastric pH and acidreflux episodes without a reduction in total reflux amount or frequency; symptoms were notassessed. Indrio, et al. conducted a randomized, double-blind, placebo-control ed trial ofeffectiveness of treatment with probiotic to establish a beneficial intestinal microbiota onfunctional gastrointestinal disorders in normal newborns. Less regurgitation was reportedby parents in the treatment group at three months, although it is not clear how much of thisrepresented GERD. Lasekan, et al., in a randomized, double-blind, placebo-control ed trial,assessed the efficacy of a low-lactose rice starch-thickened formula at reducing spittingfrequency in healthy, ful -term neonates and infants. Both groups had decreased spittingover time, with a benefit shown in the treatment group, along with high parentalsatisfaction with the thickened formula. This is an important benefit, as much of thetreatment for physiologic GER is driven by parental distress and discomfort rather thanharmful sequelae in the infant. While these studies al show promise, an importantdistinction must be made about al three: while they found a reduction in gastric acidity orregurgitation, none of them directly measured diagnosed GERD. Recent studies of proton pump inhibitor (PPI) treatment in neonates support existing dataon their ineffectiveness for treating GERD in infants.2 Despite the currentrecommendations, PPIs continue to be prescribed off-label to neonates for nonspecificsymptoms of GER and GERD.3 Esomeprazole, a PPI, is currently recommended only astreatment for erosive esophagitis in infants. Davidson, et al. conducted a randomized,double-blind, placebo-control ed phase III efficacy study using esomeprazole in pretermand term neonates who had GERD. This study was novel in including preterm infants andusing simultaneous video, cardiorespiratory monitoring, and MII with pH probe to correlatephysiologic reflux episodes with signs and symptoms of GERD. No difference was shownin GERD-related signs and symptoms with esomeprazole treatment, while increasedgastric pH was shown, consistent with the drug's mechanism of action. Hussain, et al.
conducted a randomized, double-blind withdrawal, placebo-control ed phase III efficacystudy of rabeprazole, a PPI, in infants 1-11 months with GERD. That study used validatedparent questionnaires to assess GERD symptoms. Again, no benefit was found withtreatment with rabeprazole, while improvement was shown in both groups over time. Thisstudy was novel in selecting only patients who first showed parent-reported improvementduring an open-label treatment phase, selecting for patients who have perceived benefit ofPPI. Both of these studies use validated measures to evaluate GERD and show no benefitto PPI treatment for preterm and term GERD in neonates and infants, further iterating thegrowing body of evidence against pharmacologic treatment in this group.
The final study included in this review answers an important question about prophylacticsurgical treatment of GERD in infants at high risk for GERD-related complications. Surgicaltreatment with fundoplication is considered an alternate treatment option for severe GERDand historical y has been used prophylactical y in patients considered to be at high risk for

complications related to GERD.4 Fundoplication is a highly variable practice betweencenters and pediatric surgeons. Barnhart, et al. address the use of prophylactic gastricfundoplication at the time of gastrostomy tube (G-tube) placement for enteral feeding inneurological y impaired infants, who are at high risk for GERD because of disorderedswal owing and abnormal muscle tone. This study was a retrospective observationalcohort study aimed to determine whether a benefit of fundoplication exists. No differencewas found in the first year after surgery in reflux-related hospitalization diagnoses,including pneumonia, aspiration pneumonia, esophagitis, GERD, and requirement formechanical ventilation. No distinction was made between subjects on the basis of GERDdiagnosis, so these results do not show whether the procedure is effective at treatingGERD; rather, it shows that there is no clear benefit to performing this procedureprophylactical y in this population.
Current research in neonatal and infant GERD continues to support the practice of non-pharmacologic treatment of GERD over medication. Corvaglia, et al. showed a possiblebenefit to extensively hydrolyzed protein formula, Lasekan, et al. demonstrated a reductionin physiologic GER with a low-lactose formula thickened with rice starch, and Indrio, et al.
suggest benefit of probiotic treatment of healthy, term newborns. Davidson, et al. andHussain, et al. continue to show no benefit to pharmacologic treatment of GERD in termand preterm neonates with validated measures of GERD signs and symptoms. Final y,prophylactic fundoplication to prevent GERD in infants at high risk was shown by Barnhart,et al. not to be beneficial. An important pattern, seen in many GERD treatment trials, wasshown by Hussain, et al. and Lasekan, et al. of symptomatic improvement over time,regardless of treatment. The overwhelming trend of the literature continues to support thecurrent recommendation of nonpharmacologic, nonsurgical treatment of physiologic GERand GERD in neonates and infants while awaiting physical maturation and the naturalresolution of GER and GERD.
PROPHYLACTIC SURGICAL TREATMENT FOR GERD INNEUROLOGICALLY IMPAIRED INFANTS Barnhart DC, Hal M, Mahant S, et al. Effectiveness of fundoplication at the time ofgastrostomy in infants with neurological impairment. JAMA Pediatr. 2013;167(10):911-918.
Infants with neurological impairment often have disordered feeding, swal owing and/orsevere reflux, necessitating long-term tube feeding by gastrostomy tube (G-tube). Todecrease the incidence of gastroesophageal reflux disease (GERD) and its comorbidities,some centers perform concomitant fundoplication at the time of G-tube placement to blockretrograde passage of stomach contents to the esophagus.1 In 2006 40% of allfundoplication surgeries were performed in neurological y impaired children.2 This study focused on prophylactic fundoplication at the time of G-tube placement ininfants with neurological impairment. The hypothesis of the study was that infants withneurological impairment undergoing fundoplication at the time of G-tube placement would experience fewer subsequent reflux-related hospitalizations. The study design was aretrospective observational cohort using a database of 42 freestanding, not-for-profitchildren's hospitals in the United States. Inclusion criteria were birth during the studyperiod (2005-2010), admission to a neonatal intensive care unit within the first 90 days oflife, diagnosis of neurological impairment, and G-tube placement during their initialhospitalization. No diagnosis of GERD was required. There were 2759 infants in the G-tube only group and 1404 in the G-tube and fundoplication group. The primary outcomewas hospital readmission within one year after the procedure(s) with a diagnosis related tofailure of fundoplication (esophagitis, GERD) or a pulmonary comorbidity of GERD(pneumonia, aspiration pneumonia, requirement for mechanical ventilation). Subjects who underwent G-tube and fundoplication were significantly more likely to havebeen diagnosed during the index hospitalization with pneumonia or aspiration pneumonia,more likely to have had tracheostomy placement and mechanical ventilation, and morelikely to carry a diagnosis of GERD at discharge (al P < .001) than those who underwentG-tube placement alone. Therefore, propensity-based matching was done between groupson the basis of presence of a gastrointestinal chronic condition, tracheostomy, anddiagnosis of GERD, resulting in matched groups of n = 1027. Among propensity score-matched pairs there was no significant difference in reflux-related hospital readmissionsbetween the two groups. Specifical y, no difference was found between admissiondiagnoses of pneumonia, aspiration pneumonia, esophagitis, or GERD and requirementfor mechanical ventilation. The results of this study indicate there is no benefit to routine fundoplication at the time ofG-tube placement in preventing reflux-related morbidity in infants with neurologicalimpairment. This study does not distinguish between infants who had diagnoses ofpneumonia or aspiration pneumonia prior to surgery, nor does it include patients who werereadmitted for GERD-related pulmonary complications and subsequently received afundoplication procedure. Thus, conclusions may not be drawn from the data about theeffectiveness of the fundoplication procedure itself for treating GERD, rather for its use asa prophylactic measure among infants with neurological impairment. This suggests that inthis population, routine fundoplication at the time of G-tube placement for long-term enteralfeeding should not be performed, as there is no clear benefit in the first year after surgery. EXTENSIVELY HYDROLYZED PROTEIN FORMULA TOTREAT GER IN PRETERM INFANTS Corvaglia L, Mariani E, Aceti A, et al. Extensively hydrolyzed protein formula reduces acidgastro-esophageal reflux in symptomatic preterm infants. Early Hum Dev. 2013;89:453-455.
Formula-fed preterm infants have a higher prevalence of feeding intolerance during feedadvancement than those fed fortified human milk.1 Hydrolyzed protein formulas (HPF)have been shown in preterm infants to have faster gastrointestinal transit times andaccelerated feeding advancement.2,3 The question remains whether this faster transit timereduces GERD and represents a feasible nonpharmacologic treatment option.
This was a prospective pilot study of preterm infants for whom maternal breast milk wasnot available and who had established enteral feeds with preterm formula. Infants werestarted on standard protein formula (SPF), then transitioned to extensively HPF (eHPF) ifthey had "symptoms of feeding intolerance." The aim of the study was to assess the impact of eHPF on GER symptoms in preterm infants with both feeding intolerance andGER. Inclusion criteria included gestational age ≤ 33 weeks with symptoms of feedingintolerance (defined as large gastric residuals, abdominal distension, and constipation)and GER (defined as frequent regurgitations or postprandial desaturations) as wel asweight ≥ 1100 g and currently receiving at least 100 ml/kg/day of enteral feeds. Infants ondrugs affecting gastric acidity and motility were excluded. Final study size was N = 18infants. Infants were fed eHPF for one week upon entrance to the study and according to unitprotocol. They were then given alternating feeds of eHPF and SPF while pH andmultichannel intraluminal impedance (MII) were measured to evaluate acid and nonacidGER at each feed for a 24 hour period. Caretakers and parents were not blinded to whichformula was given at each feed. The investigator who interpreted pH-impedance resultswas blinded as to which type of formula was given at each feed.
Significant differences were found in the number of acidic GER events (P = .036), definedas single detection of pH < 4, and in the reflux index (P = .044), defined as percent of timethe esophagus was exposed to pH < 4; both were lower with the eHPF feeds. No otherdifferences were found in impedance or non-acid reflux episodes. Interestingly, the results of this smal study did not show a decrease in non-acid reflux, asexpected from the previous finding of decreased gastrointestinal transit time; rather, therewas a decrease only in pH when infants were fed eHPF. This makes it a possiblesubstitute to acid-reducing medications, as this is also the desired effect of thosemedications. This study excluded infants who had not yet reached 100 ml/kg/day of enteralfeeds (who may not have advanced due to intolerance of feeds), as wel as those whowere on acid-suppressing and promotility medications. There also is a potential problemwith feeding eHPF made for term infants to preterm infants, as nutritional needs aredifferent in this population and the nutritional implications were not assessed in this study.
Notably, the study only evaluates presence of GER rather than symptomatic GERD.
Future larger studies wil be needed to assess clinical y relevant outcomes and elucidatethe mechanism of acid reduction. SAFETY AND EFFICACY OF ESOMEPRAZOLE FORTREATMENT OF NEONATAL GERD Davidson G, Wenzl TG, Thomson M, et al. Efficacy and safety of once-daily esomeprazolefor the treatment of gastroesophageal reflux disease in neonatal patients. J Pediatr.
2013;163:692-698.
Proton pump inhibitors (PPI) are recommended for moderate to severe GERD in children1-17 years of age.1 PPI treatment has general y been shown to be ineffective in reducingGERD symptoms in infants, suggesting symptoms likely result from relux volume ratherthan acidity of the contents.2 However, most investigations have not focused on neonatesor preterm infants. This study compares esomeprazole and placebo in the treatment ofGERD symptoms documented by eight-hour video and cardiorespiratory monitoring inboth preterm and term neonatal patients. The study design was a randomized, double-blind, placebo-control ed phase III studyconducted in Australia, Germany, and the United Kingdom, at one center in each country.
Inclusion criteria were postconceptional age of < 44 weeks and suspicion of any two of thefol owing: apnea, vomiting or gagging, or perceived irritability or pain with at least everyother feed or twice in eight hours. Participants were randomized to receive enteralesomeprazole 0.5 mg/kg (n = 25) or placebo (n = 26) once daily for 14 days. Simultaneouscardiorespiratory and video monitoring was performed for eight hours, and pH/impedancewas measured for 24 hours at baseline and again either at 14 days or on day ofdiscontinuation if the study ended early. The primary outcome was change from baselinein number of GERD-related signs (from video) and symptoms (from respiratorymonitoring). Secondary outcomes included mean change from baseline in signs andsymptoms of GERD by category (gastrointestinal, cardiorespiratory, and neurobehavioral).
Signs and symptoms were considered to correlate with reflux if the two occurred within twominutes of the start of an acidic reflux episode. Pharmacodynamic efficacy was measuredby number of reflux episodes of varying acidity and consistency of reflux, as wel as meanbolus and mean acid clearance time. The study found no statistical difference in the number of GERD-related signs andsymptoms between treatment and placebo groups. In both the treatment and placebogroups most symptoms improved over 14 days. No difference was found in total number ofreflux episodes, but fewer acidic (pH < 4) reflux episodes were found in the treatmentgroup versus placebo (P < .0001), consistent with the drug's mechanism of action. These data show no clinical benefit to esomeprazole. Many of the infants who hadsymptomatic GERD may not have been included because of il ness and represent a largeclinical population of neonates who routinely receive PPI treatment; conversely, welinfants may have been excluded as not expected to be hospitalized for the duration of thestudy. Additional y, patients were included only if they had at least two signs or symptomsof GERD, while clinical y patients may be treated for only one sign or symptom. Thus, as inmany trials, the study population may have limited generalizability. SAFETY AND EFFICACY OF RABEPRAZOLE FORTREATMENT OF INFANT GERD Hussain S, Kierkus J, Hu P, et al. Safety and efficacy of delayed release rabeprazole in 1-to 11-month-old infants with symptomatic GERD. J Pediatr Gastroenterol Nutr.
2014;58:226-236.
Esomeprazole is currently the only proton pump inhibitor (PPI) approved for use in infants1-11 months and is approved only for erosive esophagitis. This approval was based on theagent's ability to raise gastric pH and pharmacokinetic analysis in patients aged 1-24months,1 not on symptom reduction. Previous studies have shown no efficacy of PPIs toreduce symptoms of GERD in 1-11 month olds.2 The prevalent use of PPIs in the infantpopulation3 necessitates further investigation into whether a safe and effective PPI existsfor this population. The current study aimed to evaluate efficacy and safety of rabeprazole in infants 1-11months with GERD who previously showed symptomatic benefit with open-label use. The study design was a randomized, double-blind, placebo-controlled phase III trial. Inclusioncriteria were age 1-11 months, a diagnosis of symptomatic GERD as made by a pediatricgastroenterologist, a score of ≥ 16 on the Infant Gastroesophageal Reflux Questionnaire-Revised (I-GERQ-R), and at least one of the following: failure to thrive,irritability/crying/disturbed sleep, or food refusal/back arching. Investigators wereencouraged to choose patients who had failed nonpharmacologic management, and allother management was allowed to continue during the study period. Exclusion criteriawere known history of ALTE (apparent life-threatening event) thought to be due to GERDor other non-GERD diagnosis known to cause reflux or vomiting. Acid suppressivemedications were stopped three days prior to the first dose of study drug. The study began with an open-label phase during which all participants (N = 344) received10 mg/day of rabeprazole and were monitored with weekly I-GERQ-R scores, I-GERQ-DD(Daily Diary), and primary caregiver Clinical Global Impression of Improvement (CGI-I) forup to three weeks, to assess tolerance as well as to enrich the study population with thosewho have shown a previous response. When participants received a CGI-I score of goodor excellent (n = 268) they were then randomized to receive either 10 mg/day or 5 mg/dayof rabeprazole, or placebo for five weeks. Weekly assessments were done in person or byphone by the investigator. The primary outcome was change from baseline at the time ofrandomization in frequency of regurgitation, weight-for-age z score, weekly I-GERQ-R, anddaily I-GERQ-DD. Secondary efficacy endpoints were volume of regurgitation and specificparameters on the I-GERQ-DD. Safety was assessed with recording of treatment-emergent adverse events (TEAEs), lab tests and physical exam. No difference was found between groups from baseline to study completion in any of theprimary or secondary efficacy measures. Improvement was seen in almost everyparameter in all three groups, with no difference between treatments. Post hoc analysisseparated subjects by age and still no difference was found. Of the infants in the open-label phase, 34.6% experienced at least one TEAE, of which 4.1% were consideredtreatment related. In the blinded phase, 47% of all infants had at least one TEAE reported,one of which was thought to be possibly related to study drug in the placebo group, whileeight were thought to be related in the drug treatment groups. The caregiver-reported improvement during the run-in open-label phase of the trial can beexplained by placebo effect of entering a trial of an "experimental drug," as well as thenatural history of GERD in infants. In the randomization phase, all groups continued toimprove equally. This finding reinforces previous efficacy studies of PPIs in infant GERDand also demonstrates the role of physical maturation in improving symptoms. This studysupports the body of evidence indicating no effectiveness of PPI to improve GERDsymptoms in infants less than 12 months old, with potential adverse effects.
EFFICACY OF PROBIOTIC TREATMENT TO REDUCEFUNCTIONAL GASTROINTESTINAL DISORDERS ININFANTS Indrio F, Di Mauro A, Riezzo G, et al. Prophylactic use of a probiotic in the prevention ofcolic, regurgitation, and functional constipation. JAMA Pediatr. 2014;168(3):228-233.
Common functional gastrointestinal disorders (FGIDs) in infancy include infant colic,gastroesophageal reflux disease (GERD), and functional constipation.1 Recent studieshave suggested the importance of early colonization of the gastrointestinal tract and thesignificance of the composition of the intestinal microbiota on FGIDs.2 This study suggestsa possible role for probiotic treatment in infants to establish colonization with a healthymicrobiota to help prevent FGIDs.
This study was a prospective, multicenter, double-blind, placebo-controlled, randomizedclinical trial evaluating efficacy of newborn supplementation with Lactobacillus reuteri DSM17938 (probiotic) on development of FGIDs and on reducing the socioeconomic impact ofthese disorders. Eligibility criteria included gestational age between 37-41 weeks, age < 1week at initiation, appropriate-for-gestational-age birth weight, and 10 minute Apgar score> 8. Infants with congenital disorders were excluded. Infants were randomized to receiveeither probiotic (n = 276) or placebo (n = 278) for 90 days. The dose of probiotic was 1 x108 colony-forming units daily. Caregivers recorded daily number of regurgitations, dailyinconsolable crying time (to represent colic), and number of evacuations for the entirethree-month period. The primary outcome was change in parent-reported symptoms afterone month and three months of treatment; secondary outcomes included a cost-benefitevaluation of the supplementation, and included lost work days, medical care sought,feeding changes, hospitalizations and use of medications for gastrointestinal symptoms.
No adverse events were reported that were related to the trial.
At one month of treatment crying time was significantly decreased (P < .01) andevacuations were more frequent (P < .01) in the probiotic group versus placebo, while nodifference was found in number of regurgitations. At three months the significantimprovement in crying time and evacuations continued (both P < .01); significantly fewerregurgitation episodes were also noted (P < .01). An assessment of the secondaryoutcomes showed a significant reduction in emergency room visits, pediatrician visits,parental lost work days, and use of medications and natural or herbal products (all P <.05), with no difference in feeding changes. Cost analysis (based on costs in Italy)estimated a mean savings of $118.71 per participant for their family and a mean savings of$140.30 per participant for the community.
This study elegantly shows a benefit to immediate establishment of favorable gutmicrobiota through supplementation with probiotic in healthy, term newborns without anyapparent risk of harm. This is difficult to translate practically to use in the United States,however, because of the difficulty in obtaining a probiotic with guaranteed composition.
Additionally, no specific GERD-defining outcomes were studied, representing a futuredirection for this research to delineate whether the decreased regurgitation and cryingindicates any decrease in GERD. LOW-LACTOSE, RICE STARCH-THICKENED FORMULAREDUCES REGURGITATION IN HEALTHY INFANTS Lasekan JB, Linke HK, Oliver JS, et al. Milk protein-based infant formula containing ricestarch and low lactose reduces common regurgitation in healthy term infants: arandomized, blinded, and prospective trial. J Am Coll Nutr. 2014;33(2):136-46.
Physiologic reflux can be a source of discomfort to infants and distress to parents evenwithout harmful sequelae. Nonpharmacologic treatment of physiologic infant reflux isrecommended before pharmacologic treatment and includes positioning and other feedingstrategies, as well as thickening feeds, often with a form of rice starch.1 This study was a controlled, double-blind, randomized, multicenter trial comparing apremixed low-lactose, milk protein-based formula containing rice starch for thickenedconsistency (thickened) to a standard milk protein-based formula with lactose as thesource of carbohydrate and no rice starch (standard). The two formulas were compared forgrowth and regurgitation frequency in normal, healthy, term infants (ie, no diagnosis ofGERD) conducted at six study centers in the United States. Inclusion criteria were infantswho were healthy, singleton, gestational age of 37-42 weeks, appropriate for gestationalage, birth weight of ≥ 2500g, and age of 14 ± 3 days at study initiation. Patients could notbe on acid suppression, as gastric acidity (pH < 4) is required to fully thicken the formula.
Participants were randomized to receive thickened formula (n = 132) or standard formula(n = 132) and no other feeds during the study period. Primary outcome measures wereparental records of volume and frequency of intake, regurgitation frequency, and stoolfrequency, color, and consistency daily until 28 days of age. Parameters were alsorecorded by parents for three days prior to study visits at 2, 3, and 4 months of age.
Secondary outcome measures were parent-reported stool pattern and color, formulasatisfaction questionnaires, and growth parameters at baseline and study visits. There was no difference in weight gain between formula groups. Regurgitation frequencywas reduced in the thickened group as compared to the standard group. There was a 53%reduction at one month (P < .0005), 54% at two months (P < .001), 48% at three months(P < .003), and 32% at four months (P < .046). This study shows an improvement in spitting frequency with rice-thickened, low-lactoseformula. Importantly, parental satisfaction was increased, which often is the driving factorin formula changes and medication initiation for reflux. This study did not assess infantswith known GERD, which is an important next step to this investigation. It is also unclearwhether the improvement in the treatment group is due to thickening with rice starch or lowlactose content. Decreased spitting has previously been shown with a thickenedcommercial formula1 - this study does not clarify whether low lactose adds any benefit. Itis important to note that this study was funded by a formula manufacturer comparing oneof its products to a standard formula, presenting a potential conflict of interest. Finally, animportant trend was shown in this data with a decrease in the improvement in spitting withthe thickened formula over the four-month period, presumably because of physicalmaturation and physiologic reduction in reflux, showing that physiologic reflux decreasesover time, regardless of treatment.
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The opinions and recommendations expressed by The target audience (clinicians) for this initiative faculty and other experts whose input is included in this includes neonatologists, respiratory therapists, program are their own. This enduring material is neonatal nurses, nurse practitioners, and other produced for educational purposes only. Use of the members of the NICU team. Johns Hopkins University School of Medicine name implies review of educational format design and POLICY ON FACULTY AND PROVIDER
approach. Please review the complete prescribing information of specific drugs or combination of drugs, As a provider approved by the Accreditation Council for including indications, contraindications, warnings, and Continuing Medical Education (ACCME), it is the policy adverse effects before administering pharmacologic of the Johns Hopkins University School of Medicine therapy to patients. Office of Continuing Medical Education (OCME) to require signed disclosure of the existence of financial relationships with industry from any individual in a STATEMENT OF RESPONSIBILITY
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To access activities, users wil need: • A computer with an internet connection • An HTML5 compliant web browser or Internet Explorer 8 (and higher) All rights reserved - The Johns Hopkins University School of Medicine. Copyright 2015.
COMPLETE THE
This activity was developed in col aboration with DKBmed.
Click on link to download instructions for the post- test and evaluation Respiratory Therapists
to confirm
that your state wil
accept the CE Credits gained through this

Source: http://eneonatalreview.org/newsletters/2015/volume10_issue07.pdf