Gastroesophageal reflux (GER) is common in preterm neonates due to immature esophageal motility and lower esophageal sphincter relaxation. Diagnosis is challenging as symptoms are nonspecific. Tests include pH probes and multiple intraluminal impedance monitoring. Management follows a step-wise approach starting with non-pharmacological measures like body positioning and feeding strategies. If symptoms persist, alginate formulations, H2 receptor blockers, and proton pump inhibitors may be used though evidence for their efficacy is limited in preterms. Further research is needed to develop optimal evidence-based treatment guidelines for GER in this population.

1. Gastroesophageal Reflux (GER) in
Preterm Neonates:
An Evidence Based Therapeutic
Approach & Case Presentation
Tauhid Ahmed Bhuiyan, PharmD
Pharmacy Practice Resident (R2)
King Faisal Specialist Hospital & Research Center
(KFSH&RC)
An Application Based Activity
King Faisal Specialist Hospital and Research Center (KFSHRC) is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing
pharmacy education. (UAN# 0833-0000-15-036-L01-P, 0833-0000-15-036-L01-T)

2. Objectives
• To discuss the general overview of gastroesophageal
reflux (GER) in preterm neonates
• To identify possible diagnostic measures for
diagnosing GER
• To provide an evidenced based therapeutic approach
for management of GER
• To evaluate a topic related patient case
I do not have financial relationship and no actual or potential conflict of interest in relation to this activity

3. Important Terminologies
• Gestational age (or
“menstrual age”)
▫ First day of the last normal
menstruation to day of
delivery
• Chronological age (or
“postnatal” age)
▫ time elapsed after birth
• Prematurity:
▫ Gestational age <37 weeks
• Birth weight:
▫ Normal: 2500 g +
▫ Low: <2500 g
▫ Very low: <1500 g
AAP. Age Terminology. Pediatrics 2004; 114:1362–64

4. Definition
• “Gastroesophageal reflux (GER) is the passage of gastric
contents into the esophagus with or without regurgitation
and vomiting”
• “Gastroesophageal reflux disease (GERD), when reflux of
gastric acid contents causes troublesome symptoms
and/or complications”
Vandenplas Y et al. J Pediatr Gastroenterol Nutr 2009; 49:498–547

5. Gastroesophageal Reflux (GER)
• Common phenomenon in all newborn infants, especially
in premature babies
• Normal physiological process associated with transient
relaxation of the lower esophageal sphincter (LES)
• Associated factors in premature babies
▫ Posture
▫ Immature esophageal motility
▫ Abundant milk intake
• “Regurgitation” and “spitting up” are the two most
visible symptoms
Lightdale JR et al. Pediatrics 2013; 131(5):e1684-95

6. Regurgitation
• “Passage of refluxed gastric contents into the pharynx
or mouth and sometimes expelled out of the mouth”
• Regurgitation is generally assigned as effortless and
non-projectile
• Occurs daily in about 50%of the infants < 3 months
of age
• Resolves spontaneously in most healthy infants by 12
to 14 months of age
Vandenplas Y et al. J Pediatr Gastroenterol Nutr 2009; 49:498–547

7. Epidemiology
• Occurs in all healthy infants ≥30 times daily that lasts <3 mins
(“happy spitters”)
• Common: healthy preterm > term
• Dhillon AS et al., one year multicenter observation study (77 NICU in
England and Wales) using standard questionnaire
▫ The incidence of symptomatic GER in those babies born before 34 weeks of gestation
~22%
▫ Common treatment strategies:
 Body positioning (98%)
 Placement on a slope (96%)
 H2-receptor antagonists (100%)
 Feed thickeners (98%)
 Antacids (96%)
 Prokinetic agents (79%)
 Proton-pump inhibitors (65%)
 Dopamine-receptor antagonists (53%)

8. Incidence of GERD
• Babies with history of regurgitation, the peak prevalence
of GERD,
▫ ~50% at 4 months of age
▫ 5% to 10% of infants at 12 months
• Prospective birth cohort study (n=693) in children who
were followed for 2 years from birth and then contacted 8
to 11 years later
▫ Children with history of frequent regurgitation (defined as >90
days of "spilling out" during the first two years of life) were
relatively 2.3 times higher likelihood of reporting GERD
symptoms during follow-up years (95% CI 1.3-4.0)
Dhillon AS et al. Acta Paediatr 2004;93(1):88-93
Martin AJ et al. Pediatrics. 2002;109(6):1061

9. Pathogenesis of GER in Premature
Babies
“Multifactorial”
• Relaxation of lower esophageal sphincter (LES)
▫ Linked to 92-94% of the overall GER episodes
• Gastric emptying ( ↑time ≈ ↓gestational age)
• Esophageal motility
• Respiratory disorders (e.g. BPD)
• Gastric tube (e.g. naso/oro gastric tube)
▫ Cause ↑ LES relaxation and/or ↓ gastric emptying
BPD: bronchopulmonary dysplasia

10. Complications
• Frequent feeding problems
• Failure to thrive
• Esophagitis
• Lung aspiration wheezing or pneumonia
▫ Can increase the length of hospitalization
• Apnea & chronic lung disease; still controversial
Corvaglia L et al. Gastroenterology Research and Practice 2013

12. Diagnostic Evaluations
• Constant challenge
• Symptoms are nonspecific and diagnostic tests are limited
due to
▫ Sensitivity and Specificity
▫ Condition of the babies
History & Physical Examination
▫ Nonspecific signs: regurgitation of milk, vomiting, irritability,
unexplained crying, arching, grimace, desaturation, sleep
disturbances, feeding refusal, or respiratory symptoms
▫ Differential diagnoses: bilious vomiting, gastrointestinal bleeding,
diarrhea, constipation, fever, lethargy, abdominal tenderness and
distension, and hepatosplenomegaly
Martin R. et al. Gastroesophageal reflux in premature infants. Uptodate.
Accessed on: May 13, 2015

13. Available Tests
• Esophageal pH probe (most widely used
in preterm)
▫ Detect reflux of gastric contents (pH <4)
▫ Trans-nasal passage of microelectrode to measure pH
▫ Limitation: detection of acid refluxes only
• Multiple intraluminal impedance (MII)
▫ Higher sensitivity compared to pH probe
▫ Detect both acidic and non-acidic fluid, solids, and air
• Combination of latter two
▫ Best diagnostic choice, detects acid, weakly acid, and nonacid reflux
episodes
▫ Recognized by both NASPGHAN & ESPGHAN
NASPGHAN: North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
ESPGHAN: European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition
Martin R. et al. Gastroesophageal reflux in premature infants. Uptodate.
Accessed on: May 13, 2015

14. Management
Step-wise Approach:
1st line: Non-pharmacological
2nd line: Pharmacological

15. Guidelines
2009
2013

16. Goals of Therapy
• Short term:
▫ Minimize signs and symptoms
▫ Prevent adverse drug reactions
▫ Improve health related outcomes (e.g. weight gain)
• Long term:
▫ Prevention of development of GERD

17. Non-pharmacological Therapy
• First-line treatment in symptomatic babies who are
experiencing frequent vomiting and effortless
regurgitations without significant clinical complications
• Available options:
Corvaglia L et al. Gastroenterology Research and Practice 2013
Body positioning
Feeding strategies
Feed thickening
Hydrolyzed formulas

18. Body Posture
• Widely used: prone or left-side positions
• Ewer et al. [1999] studied prospectively using 24h
lower esophageal pH monitoring in 18 preterm (<37
weeks of gestation) who received full feeds (150
ml/kg/day)
▫ Infants were nursed for 8 hours in three positions (prone,
left, right lateral)
▫ Results:
Ewer AK. et al. Arch Dis Child Fetal Neonatal Ed 1999;81:F201–F205

19. Body Posture Cont.
• Omari TI et al. [2004] combined esophageal
manometry and MII to investigate the efficacy of left vs.
right lateral position on GER in 10 healthy preterm
(35-37 wks)
▫ Compared to right lateral position, left lateral position had
significantly less
 GER (P < .01)
 Higher proportion of liquid GER (P < .05)
 Faster GE (P < .005)
Omari TI. et al. J Pediatr 2004;145:194-200

20. Feeding Strategies
• Feeding frequency:
▫ Omari et al. [2002] observed a positive correlation between
the frequency of feedings (every 2,3,or 4 hrs) and the
occurrence of nonacid GER episodes with concomitant
decrease in acidic GER episodes in mildly symptomatic infants
▫ Study recommendation: frequent, small volume feeds may
improve GER
• Bolus vs. continuous tube feedings
▫ Assessed by Jadcherla et al. [2012]: found a significant negative
correlation (P < .03) between feeding duration and total GER
events, number of nonacidic GERs
▫ Useful strategy: reduction in feeding flow rate (mL/min)
Corvaglia L et al. Gastroenterology Research and Practice 2013

21. Available Pharmacological
Options
1. Alginate-based formulations
2. Histamine-2 receptor blockers
3. Proton pump inhibitors
4. Prokinetic agents

22. Alginate-Based Formulations
• Reported to be the most commonly prescribed anti-
reflux medication in preterm infants with symptomatic for
GER
• Mechanism of action:
▫ Forms low density but viscous foamy gel in the presence of gastric
acid
▫ Floats on the surface of gastric content during GER episodes
• Available forms:
▫ Sodium alginate + sodium bicarbonate (Gaviscon®)
• Adverse drug reactions:
▫ “Aluminum toxicity”, abdominal distension, hypernatremia,
constipation (products contain aluminum), thickening of the stool
and anal fissure
Corvaglia L et al. Gastroenterology Research and Practice 2013

23. Clinical Evidence
• Limited data
• Covaglia et al. [2011] evaluated the efficacy sodium
alginate (Gaviscon®) using a 24 h pH-MII in 22
symptomatic preterm newborn
▫ Sodium alginate was given 4X at alternate meals [drug-given
(DG) vs. drug-free (DF) meals] and was found to have significant
effect in decreasing the number of GER detected either by:
 pH monitoring (DG vs. DF: median 17.00 vs. 29.00, P = 0.002)
 MII (DG vs. DF: 4.0 vs. 6.00, P = 0.050)
 Acid esophageal exposure (DG vs. DF: 4.0% vs. 7.6%, P = 0.030)
Corvaglia L et al. Gastroenterology Research and Practice 2013

24. H2RA
• FDA approved in ages ≥ 1 month
• Mechanism of action:
▫ Decrease acid secretion by inhibiting the histamine-2 receptor on the
gastric parietal cells
• Available forms:
▫ Ranitidine, famotidine, cimetidine, nizatidine
• Adverse drug reactions:
▫ New evidence:
 Linked to infection (in VLBW) and development of necrotizing
enterocolitis (NEC)
▫ Increased risk of liver disease and gynecomastia (cimetidine)
Corvaglia L et al. Gastroenterology Research and Practice 2013

25. Clinical Evidence
• Efficacy of use in preterm, “an
issue of debate”
• Kuusela AL et al. [1998] studied
the optimal doses of ranitidine
for both preterm and term
infants
▫ 16 preterm (gestational age under 37
weeks) and term infants treated with
three different bolus doses of
ranitidine (0.5 mg, 1.0 mg, and 1.5
mg per kg)
▫ Results:
Corvaglia L et al. Gastroenterology Research and Practice 2013
Premature & term neonates <2 weeks:
Oral: 2 mg/kg/day divided every 12
hours
IV: 1.5 mg/kg/day loading followed by
maintenance dose every 12 hours

26. H2RA & NEC
• Guillet et al. [2006] performed a retrospective case-
control study on VLBW infants to investigate the
association between the incidence of NEC and the use of
H2-blockers, as ranitidine, famotidine, and cimetidine
▫ Found overall incidence of NEC of 7.1%, especially with longer
duration (18.9 ± 15.5 days)
• Recent study [2012] confirmed by Terrin et al.
▫ NEC was more frequent in infants treated with ranitidine (rate
9.8%) compared to those who did not (rate 1.6%)
• Latest evidence [2013] by Bilali et al.
▫ NEC in preterm infants treated with ranitidine when compared to
the control group (17.2% vs. 4.3%)
Corvaglia L et al. Gastroenterology Research and Practice 2013

27. PPI
• Not approved for children <1 year and clinically
ineffective to relieve GER symptoms
• Mechanism of action:
▫ Blocks gastric proton pump that catalyzes the final phase of the
acid secretory process of parietal cells
• Available forms:
▫ Omeprazole, esomeprazole, rabeprazole, lansoprazole,
pantoprazole
• Adverse drug reactions:
▫ Headache, diarrhea, constipation, and nausea (2% to 7%)
▫ Growing evidence of NEC & hypochlorhydria
Corvaglia L et al. Gastroenterology Research and Practice 2013

28. Clinical Evidence
• Data on the safety and efficacy of PPIs in the preterm
population are few and somewhat controversial
• Omari et al. [2007] conducted 2-week randomized,
double blinded, placebo-controlled trial for effectiveness
of omeprazole [dose: 0.7 mg/kg/day] on preterm infants
(n= 10) with GERD
▫ Omeprazole therapy significantly reduced gastric acidity (%time
pH <4, 54% vs 14%, P < 0.0005)
▫ Esophageal acid exposure (%time pH <4, 19% vs 5%, P < 0.01)
▫ Number of acid GER episodes (119 vs 60 episodes, P < 0.05)
▫ Limited by lack of sample size
Corvaglia L et al. Gastroenterology Research and Practice 2013

29. Clinical Evidence
• Moore DJ et al. [2003] conducted a double-blinded,
randomized, placebo-controlled trial to assess the efficacy
of omeprazole with GER and/or esophagitis in 30 irritable
infants (3-12 months)
▫ Using visual analogue scale, irritability were measure at baseline
and the end of each 2-week treatment period
▫ Results:
 Reflux index fell significantly during omeprazole treatment vs. placebo (-
8.9% ± 5.6%, -1.9% ± 2.0%, P < .001)
 VA score (assessed by parents) for the level of irritability while taking
omeprazole or placebo did not differ significantly (n = 30, 5.0 ± 3.1
versus 5.9 ± 2.1, P = .214)
• No difference in GER reduction between lansoprazole
(54%) vs. placebo (54%) (Orenstein SR et al. [2009])
▫ Rate of respiratory infection was higher in lansoprazole group
(10 vs 2; P= .032)
Corvaglia L et al. Gastroenterology Research and Practice 2013

30. Prokinetic Agents
• Improve gastric emptying, to reduce emesis, and to
enhance LES tone
• Agents
▫ Cisapride
▫ Domperidone
▫ Erythromycin
▫ Metoclopramide
Corvaglia L et al. Gastroenterology Research and Practice 2013

31. Cisapride (Propulsid®)
• Largely investigated
• Mechanism of action:
▫ Enhance the release of acetylcholine from the mesenteric plexus
decreasing GER
▫ Antagonist of the rapid component of the delayed rectifier current of
potassium in cardiac cells (antiarrhythmic effect)
• Ariagno et al. [2001] demonstrated
▫ A significant reduction in reflux indexes and in the number of GER
episodes lasting ≥5 minutes
▫ Ineffective on the total number of refluxes/24 hours and on the
duration of the longest episode
• Dose dependent QTc prolongation and cardiac
arrhythmias—no longer used for GER
Corvaglia L et al. Gastroenterology Research and Practice 2013

32. Domperidone (Motilium®)
• Mechanism of action:
▫ Blocks dopamine receptors in chemoreceptor trigger zone of the
CNS
 Enhance the response to acetylcholine of tissue in upper GI tract
causing enhanced motility and accelerated gastric emptying without
stimulating gastric, biliary, or pancreatic secretions
• Few evidence in infants and children but none for
preterm infants
• Safety alerts:
▫ Increased risk of serious adverse cardiac effects including dose
dependent QTc prolongation, arrhythmias and sudden
cardiac death
Corvaglia L et al. Gastroenterology Research and Practice 2013

33. Erythromycin
• Mechanism of actions:
▫ Strong non-peptide motilin receptor agonist that contributes to
enhance gastric emptying and intra-digestive migratory motor
complex
• Although use of erythromycin large randomized
controlled trial demonstrated significant improvement on
parenteral-nutrition associated cholestasis in preterm
infants, however, no significant improvement were found
in resolution of GER
• Adverse drug reactions:
▫ Reported cases of increased risk of infantile hypertrophic
pyloric stenosis (especially use during the first 2 weeks of life)
▫ Reported cases of cardiac arrhythmias
Corvaglia L et al. Gastroenterology Research and Practice 2013

34. Metoclopramide (Reglan®)
• Mechanism of action:
▫ Similar to domperidone
• A Cochrane review published in 2004 affirmed the
effectiveness of metoclopramide in reducing both clinical
symptoms and reflux indexes in infants with GERD, but
limited by
▫ Conflicting results of the studies
▫ Lack of a valid demonstration of the metoclopramide‘s efficacy or
toxicity
• Adverse drug reactions:
▫ Irritability (most frequent), followed by dystonic reactions,
drowsiness, oculogyric crisis, emesis, and, eventually, apnea
Corvaglia L et al. Gastroenterology Research and Practice 2013

35. By now, you are probably here??

36. Take Home Message
• Although GER is very common condition among preterm
infants with unclear treatment management,
▫ Therapy should be tailored based on clinical presentation and
complications
▫ Nonpharmacological management should be considered as
first line
 “happy spitters”
▫ To avoid any harmful overtreatment, pharmacological
therapy should strictly be limited to selected infants suffering
from GER complications or failure of conservative measures
▫ When choosing pharmacological options:
 Consider risk vs. benefit ratio based on current evidence

37. Pharmacist Role
• Provide evidence based guidance for selection of
appropriate pharmacotherapeutic agents
• Identify inappropriate doses, drug-drug
interactions, or dose adjustments (if necessary)
• Monitor adverse drug reactions
• Provide bedside teaching to other health care
providers (when necessary)
• Provide discharge counselling to the parents and/or
caregivers

38. Patient Case
• SS, B.Boy twin II, preterm (32 weeks) delivered on 18th of April from an
unbooked mother as a case of emergency C/S
• Mother: 19 yo Saudi, female married to her 1st cousin, no known chronic
illness, G1P2 + 0
• At birth:
▫ Apgar score: 6 in 1 min, 8 in 5 min
▫ Vital: Temp: Afebrile | HR 120 bpm | BP: 45/25 mmHg | RR: 40 brths/min | O2 Sat:
92% RA
▫ Physical exam: unremarkable, head circ: 29 cm, abd girth: 20.5 cm (non distended)
▫ Case of very low birth weight (VLBW): 1.13 kg
• NKA
• After birth, developed mild respiratory distress
• Shifted to NICU with high flow nasal cannula (7 L/min)

39. NICU, Day 0
• Reason for admission: prematurity, R/O of sepsis, mild RDS, VLBW
• Physical Exams:
• Skin: normal
• CNS: active baby
• Chest: clear, on 1 L/min NC, FiO2: 21%
• CVS: S1 + S2+ 0; not on any inotropes
• Vitals: Temp: 36.5 | HR 125 bpm | BP: 52/25 mmHg | RR: 65 brths/min on | O2 Sat:
92% RA
• GI: soft + lax; NPO, TPN (10% dextrose) + Lipids (2.5 gm/kg)
• TFI: 70 mL/kg/day
• Medications:
• Ampicillin 55 mg IV q12h; Gentamicin 5 mg IV q36h, Caffeine Citrate 22 mg IV load
followed by 6 mg IV daily, Hepatitis B immunoglobulin 100 IU IV once
• Assessment: Stable patient with no active issues
• Plan: Start feeding after placing OGT; US (head) next week

40. NICU, Day 1
• CNS: active, moving all four limbs
• CVS: HD stable; BP: 60/29 mmHg; HR: 130’s
• Resp: On 0.5 L/min NC; on/off tachypnea; O2 sat: 98%
• GI: started feeding according to the protocol; UOP: 3.9 ml/kg/hr
• Lab:
• Medication: same
• Assessment: stable
• Plan:
▫ Keep O2 sat >92% with supplemental oxygen
▫ CXR, CBC daily, CRP, blood culture, blood glucose q8h
▫ Continue same management & increase TFI to 110 mL/kg/day
Na: 145 K: 4.8 Cl: 110 CO2: 19.2 BUN: 3.2 Cr: 82
WBC: 5 Hgb: 16.7 Hct: 46.7 Plt: 179 Glu: 3.1 Ca: 2.33
PO41.62 Alb: 31 ALP: 198 AST: 5 Tot. Bill: 84.3

41. NICU, Day 2
• CNS: very active; Temp: afebrile
• CVS: HD stable; BP: 55/32 mmHg; HR: 130’s
• Resp: still on NC; RR: 65-32; O2 sat: 95%
• GI: feeding per protocol; UOP: 3.8 ml/kg/hr; Abd girth: ↑ 1.5 cm and no
passage of stool
• Lab: unremarkable; ROP: negative; Blood culture: no growth
• Medication: same
• Assessment: stable, mild RDS
• Plan:
▫ D/C antibiotic; oxygen
▫ Glycerin suppository once as needed
▫ Preparation for transfer to HDU

42. NICU, Day 3-5
• CNS: no complaints; head circ: same
• CVS: stable; BP: 60’s/30’s mmHg; HR: 130’s
• Resp: At RA with occasional tachypnea; RR: 32-60 brth/min; O2 sat: >95%
• GI:
▫ On full feed (5-10 mL q2-3h); TPN + lipid (same), Wt: 1.02 kg (↓ by 10 gm)
▫ Abd girth: ↑ 1.0 cm; not passing stool
▫ Vomited once (small amount)
• UOP: ~3 mL/kg/hr
• Medication: Caffeine Citrate 6 mg PO once daily
• Plan:
▫ TFI ↑sed to 140 mL/kg/day; kept on prone position; d/c TPN

43. NICU, Week 2 (24/04—29/04)
• CNS: unremarkable CVS: stable; BP: 60’s-70’s/20’s-30’s mmHg; HR: 130-190 bpm
• Resp: on RA; RR: 32-45 brth/min; O2 sat: 100%
• GI:
▫ Abd: soft + lax; passed stool; girth: same
▫ Feed ↑ to 13 mL q2-3h
▫ Patient kept on elevated, right lateral prone position (26/04)
▫ Frequent regurgitation and vomiting (milk); multiple times a day; feed refusal
▫ Started feed thickening on 26/04
• Lab: Wt gain: static (1.116 kg)
• Medication: Caffeine Citrate 6 mg PO once daily; Ranitidine 0.56 mg IV q12h
(27/04)
• Plan:
▫ Continue same management; head US to R/O IVH; shift to HDU
Na: 139 K: 5.8 Cl: 97
CO2: 19.9 BUN: 2.2 Cr: 58
Vomiting
Frequency
26/4 27/4 28/4 29/4
2X 3X 2X --

44. Continuation of Care
• HDU: Stable over the weekend; active; not crying
• CNS + CVS: unremarkable; BP: 50-60’s/20-30’s; HR: 130-140 bpm
• Resp: on RA; RR: 35-40; O2 sat: >98%
• GI: Wt: 1.190 kg (↑ 70 gm)
▫ Abd: soft + lax; passing stool
▫ No reports of regurgitation or vomiting
• TFI: 150 mL/kg/day
• UOP: 6.4 mL/kg/hr
• Lab: unremarkable; US: negative for IVH
• Medication: Caffeine Citrate 6 mg PO once daily; Ranitidine 0.8 mg PO q12h
• Plan:
▫ Start Ranitidine 2 mg PO q8h X 2-3 days if no vomiting, weight gain, improvement of
feeding