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