REVIEW

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Gastroesophageal reflux disease in the

neonatal intensive care unit
Arianna Aceti†1 & Luigi Corvaglia1
Gastroesophageal reflux (GER), commonly diagnosed in preterm infants in neonatal intensive care
units (NICUs), is a cause of morbidity and is known to prolong hospital stay. Pharmacological
treatment of presumed or proven GER is increasingly being used in NICUs; this attitude is concerning,
owing to an association between pharmacological treatment of GER and serious adverse events,
which has recently been demonstrated (i.e., ranitidine and necrotizing enterocolitis). Furthermore,
a wide variability exists among NICUs in the proportion of infants treated for GER, which suggests
a serious lack of evidence in this field. Thus, there is a need to develop safe and effective treatment
options for GER in preterm infants is a critical issue for future research.

Gastroesophageal reflux (GER) is the passage
of gastric content into the esophagus with or
without regurgitation and vomiting. It is a nor-
mal physiologic process occurring several times
per day in healthy infants, children and adults.
By contrast, GER disease (GERD) occurs when
the reflux of gastric contents causes ­troublesome
symptoms and/or complications [1] .
Gastroesophageal reflux disease is a com-
mon diagnosis in neonatal intensive care units
(NICUs). The incidence of GER in preterm
infants is believed to be higher than that in
term infants. A survey conducted among 77
level II or III NICUs in England and Wales has
shown that GER is perceived by neonatologists
as a common problem affecting approximately
one-fifth of infants born before 34 weeks’
gestational age [2] . However, the survey also
highlights that a wide variability among indi-
vidual centers in diagnostic and thera­p eutic
strategies for GER exists, thus, the correct
diagnosis is a critical issue that a neonatologist
has to address when evaluating an infant with
suspected GER.
In preterm infants, GER is favored by large
milk intake, tube feeding and the lying posi-
Furthermore, many drugs are commonly
used in preterm infants with the presumed diag-
nosis of GER, during hospital stay in NICU
and also after discharge. Recently, Malcolm
et al. reported that approximately one-fourth
of extremely low birthweight (ELBW) infants
are discharged from hospital with medications
to treat GER  [6] . This attitude is concerning,
because recent evidence suggests an associa-
tion between the use of different drugs and
serious adverse effects (e.g., tranitidine and
necrotizing enterocolitis [NEC]) [7–9] . The
study by Malcolm et  al. also highlights an
enormous degree of variation among centers
(from 2 to 90%) in the use of GER medications
in preterm infants discharged at more than
42 weeks postmenstrual age, which implies a
“serious lack of evidence to guide practice or
ignorance of evidence that would suggest one
extreme or the other – use or nonuse” [10] .
1
Neonatology & Neonatal Intensive
Signs & symptoms of GER Care Unit, S Orsola-Malpighi Hospital,
Clinical presentation of GERD in preterm University of Bologna, Bologna, Italy
†
Author for correspondence:
infants is often subtle and reflux-specific behav- Tel.: +39 051 342 754
iors have been shown to be unreliable indica- Fax: +39 051 342 754
tors of GER in this population [11] . The survey arianna.aceti@gmail.com

tion  [3] . Pathophysiological mechanisms of conducted by Dhillon and Ewer in 48 NICUs

GERD have recently been studied in infants,
and transient lower esophageal sphincter relax-
ations (TLESRs) have been shown to be the
major contributing factor in both preterm and
term infants, while the role of delayed gastric
emptying still remains controversial [4] .
Gastroesophageal reflux disease in NICUs
causes morbidity and has been reported to pro-
long hospital stay; some authors have hypoth-
esized that it could be linked to apnea of prema-
turity (AOP), worsening chronic lung disease,
aspiration of gastric contents and esophagitis [5] .
in England and Wales reported clinical symp-
Keywords
toms and signs that were considered indicative
for GER by neonatologists [2] . These included • apnea of prematurity
vomiting, feed intolerance and regurgitation as • combined multichannel
intraluminal impedance
the most commonly considered symptoms to be
• conservative treatment
GER-related (71% of the responded question- • gastroesophageal reflux
naires). Furthermore, ‘atypical’ symptoms, such • pH monitoring
as apnea and bradycardia, were often reported
(69 and 48%, respectively).
Birch and Newell have recently proposed a part of
reflux scoring system specifically designed for
preterm infants [5] , adapted from the Orenstein’s

10.2217/PHE.10.38 © 2010 Future Medicine Ltd Pediatric Health (2010) 4(4), 405–412 ISSN 1745-5111 405
REVIEW – Aceti & Corvaglia
Infant Gastroesophageal Reflux Questionnaire
Revised (I-GERQ-R). The I-GERQ was origi-
nally modified from a questionnaire designed
for completion by primary caregivers in term
infants suspected of GERD and assessed for
diagnostic validity by comparison with normal
controls; then, it was further modified to pro-
duce the I-GERQ-R in order to evaluate the
response to treatment [12] .
This questionnaire investigates the presence
of GER by evaluating primarily typical symp-
toms of GER, such as frequency and degree
of regurgitation, chewing, crying between
feeds, hiccupping and back arching. In addi-
tion, the authors also included in the scoring
system atypical symptoms such as apneas,
bradycardia and desaturations occurring in the
15 min after feeding. Once validated, such a
questionnaire could represent a useful tool for
the diagnosis and the management of GERD
in preterm infants, and would limit the use of
invasive diagnostic ­techniques only to severe or
complicated disease.
Both GER and AOP are frequent in preterm
infants, and many neonatologists believe that
apneas and bradycardia, especially when they
occur in postprandial periods, can be con-
sidered as symptoms of GER in this popula-
tion. The pathophysiological and clinical link
between these events has been hypothesized
frequently  [13] , but it remains unclear whether
a temporal relationship really exists [14–16] .
Experimental studies performed on animal
models have investigated the pathophysiology
of this relationship, showing that the infusion
of a liquid solution into the larynx or esoph­agus
evokes the so-called chemolaryngeal reflex,
which can cause apneas and swallows [17–19] . A
reflex evoked by water stimulation in the mid-
esophagus and characterized by the occurrence
of central apneas, swallows and alteration of
esophageal motility has also been described [20] .
Clinical studies aiming to investigate this
relationship have obtained conflicting results:
specifically, the studies by Peter [14] and Di
Fiore  [15] have excluded the existence of a tem-
poral link between GER and AOP in preterm
infants, while Corvaglia et al. have demonstrated
that, in preterm infants with recurrent apneas,
these events occur more frequently soon after
GER than in the period immediately before,
thus speculating that the relationship between
GER and AOP is not simply by chance [16] .
When comparing the results of clinical studies
investigating GER and AOP, one of the main
difficulties is that different studies use different
406 www.futuremedicine.com
techniques for either GER and apneas detection.
Furthermore, many studies use techniques that
are inadequate for the detection of nonacid GER,
which occurs most likely immediately after a milk
meal. In conclusion, as stated by Slocum et al. in a
recent paper, “...currently available evidence sug-
gests that most reflux events do not cause apnea
in most infants but that some reflux may cause
apnea in some infants” [13] . Thus, in order to draw
definitive conclusions, future studies are needed
to define specific reflux or patient characteristics
that increase the risk of reflux-induced apneas.
The relationship between GER and brady­
cardia in preterm infants has been also investi-
gated, and, as for apnea, no definitive conclu-
sion has been drawn. Slocum et al. tested in
36 preterm infants the hypothesis that the rates
of GER, apnea, bradycardia and desaturations
increase after feeding; however, feeding was
found to significantly increase the frequency,
pH and bolus height of GER, but despite this no
concomitant increase in cardiorespiratory events
was documented [21] . It has also been investigated
whether antireflux medications are able to reduce
bradycardia attributed to clinically suspected
GER. Specifically, Wheatley et al. showed that
metoclopramide and ranitidine do not reduce
apnea and bradycardia events or improve the
outcome of preterm infants [22] , which supports
the growing literature according to which there
is a potentially harmful ­overtreatment of GER in
preterm infants [6] .
Even more controversial is the correlation
between GER and bronchopulmonary dysplasia
(BPD): recent studies highlighted that pepsin,
which is a marker of gastric content, is increased
in tracheal aspirates from preterm infants
who develop BPD, thus suggesting a potential
pathogenetic role of GER in BPD [23] .
Diagnosis of GER
Since the 1980s, 24 h esophageal pH monitoring
has been generally accepted as the gold-standard
technique for the diagnosis of GER, both in adult
and in pediatric patients [24] . This technique rec-
ognizes GER as a drop in esophageal pH to less
than 4; thus, it detects acid GER, whereas it is
unable to identify nonacid GER. This limitation
is particularly relevant in preterm newborns,
because milk feeding buffers gastric pH and thus
masks the detection of reflux [25] . Therefore, pH
monitoring has crucial limitations when applied
to preterm infants because it may underestimate
the frequency of reflux episodes and may not
identify cardiorespiratory events resulting from
nonacid reflux [26] .
future science group
 Gastroesophageal reflux disease in the neonatal intensive care unit –
Multichannel intraluminal impedance (MII)
monitoring is a new technique that can be used
to detect the flow of fluids and gas through
hollow viscera. Thus, GER is detected by MII,
regardless of its acidity, by differences in elec-
trical impedance between the mucosal surface,
and by fluids and gas that surround the cath-
eter  [27] . MII is highly sensitive to very small
fluid bolus movements [28] , permits to distin-
guish retrograde bolus movement (GER) from
antegrade movement (swallow), recognizes
physical composition of refluxate and records
the distance from lower esophageal sphincter
(LES) reached by each GER episode.
In adult patients, combined MII and pH
monitoring (pH‑MII) is emerging as a useful
tool to study both acid and nonacid reflux, pro-
viding detailed characterization of the reflux
episode, including determination of the compo-
sition (gaseous, liquid or mixed) and the height
reached by the refluxate [29] . By this combined
technique, GER is primarily detected by MII as
a rapid retrograde fall from a pre-episode base-
line impedance to 50% or less of the baseline
period, on two or more sequential channels.
The GER event is then identified as acid or
nonacid according to the associated pH change.
It should be noted that this method to detect
acid reflux, which is different from that used by
conventional pH monitoring, can result in dis-
crepancies in the number of acid reflux events
reported by these two techniques [30] .
These discrepancies were studied by Corvaglia
et al., who compared in 52 preterm infants two
options for the analysis of pH‑MII layout. The
first included GER episodes detected by MII
and then classified as acid or nonacid accord-
ing to the associated pH change, whereas the
second option included GER episodes detected
by MII and also GER episodes detected by con-
ventional pH monitoring [31] . The use of the
second option allowed the detection of an aver-
age of 53.2 acid GER episodes and an average
of 11% esophageal exposure to acid GER more
than the first option. Thus, the authors con-
cluded that an accurate and detailed descrip-
tion of GER in preterm infants must take into
account all acid GER episodes, which include
those detected by MII and those detected by
conventional pH monitoring. Furthermore,
by utilizing pH‑MII it was possible to analyze
how chemical features of GER changed over
postprandial periods. Specifically, the authors
found that nonacid GER was significantly more
common immediately after feeds, while acid
GER prevailed in the late postprandial period.
future science group Pediatric Health (2010) 4(4)
Review
Di Fiore et al. evaluated possible etiologies
of acid reflux events detected by conventional
pH monitoring and not identified by combined
pH‑MII [30] . They studied 80  preterm and
39 term infants by combined pH‑MII and found
that 59% of acid GER episodes detected by con-
ventional pH monitoring was not identified by
combined pH‑MII. Furthermore, the incidence
of acid episodes undetected by MII was higher
in preterm than in term infants, probably due to
immature peristalsis of the esophagus and gas-
tric emptying. The authors also investigated why
MII was unable to detect some GER episodes, and
found that 64% of GER episodes were missed due
to no change in impedance, 13% due to failure to
meet MII scoring threshold, 12% due to technical
artefacts and 11% to an air bolus. The authors
concluded that MII should not be the primary
diagnostic technique for GER detection in new-
borns and that acid reflux events detected either
by MII or by pH monitoring should be considered
when using pH‑MII in preterm infants.
Treatment of GER
The treatment of GER in preterm infants is a
challenging issue, because treatment options
and the support of good quality evidence in this
population are limited. However, few medical
conditions are treated in such a large proportion
of patients without clear diagnostic criteria [5,6] .
The association between GER overtreat-
ment and adverse effects suggests that, for pre-
term infants with pathologic GER, a stepwise
approach with initial conservative intervention
is probably the best therapeutic choice.
Conservative treatment
Conservative interventions include body
positioning [32–35] , the use of frequent and
low-volume feeds  [4] , and the thickening of
feeds [36–38] .
Body positioning
The effect of body positioning on gastro-
esophageal reflux and gastric emptying (GE)
in preterm infants has been investigated in two
recent studies [33,34] by combined manometry
and impedance monitoring, a technique that
allows the determination of the relation between
esophageal, LES and gastric pressure and GER
features (i.e., occurrence, nature, duration and
proximal extent). The first study investigated
the occurrence of GER by MII in ten healthy
preterm infants and aimed also to characterize
the mechanisms of GER triggering and GER
clearance by manometry and C13Na-octanoate
407
REVIEW – Aceti & Corvaglia
breath test. The authors confirmed that TLESRs
were the predominant mechanism of GER; fur-
thermore, they found that infants studied in the
right lateral position (RLP) had significantly more
GER, despite a faster GE, when compared with
infants in the left lateral position (LLP) [33] . The
second study specifically investigated the role
of body positioning on GE and GER. A total
of ten healthy preterm infants were studied, by
combined manometry and impedance monitor-
ing, in two different body positions (LLP and
RLP). Infants were positioned in LLP or RLP
and then gavage-fed. After 1 h, the position was
changed to the opposite side; all infants were stud-
ied a second time, with the order of positioning
reversed. The authors found a higher number of
liquid GER in RLP than in LLP; furthermore,
in the RLP-first protocol the number of liquid
GER decreased significantly when position was
changed from RLP to LLP and GE was faster than
in the LLP-first protocol. The practical clinical
suggestion that emerged from these data would
be to position healthy preterm infants in RLP for
the first postprandial hour and then change the
position into LLP in order to promote GE and
also to reduce liquid GER in the late postprandial
period [34] . Corvaglia et al. evaluated the effect of
four different body positions (supine [SP], prone
[PP], RLP and LLP) on acid and nonacid GER
by combined pH‑MII in 22 symptomatic, very
preterm infants. Mean esophageal exposure to
acid and nonacid GER were lower in PP and LLP
than in RLP and SP. During postprandial peri-
ods, the number of nonacid GER decreased over
time, while the number of acid GER increased.
Furthermore, the lowest esophageal acid exposure
was documented in LLP in the early postprandial
period and in PP in the late postprandial period.
The authors concluded that placing symptomatic
preterm infants in PP and/or LLP after feeding
could represent an easy conservative strategy for
reducing GER [35] . It should be highlighted that,
as PP is associated with sudden infant death syn-
drome [39] , such a postural intervention can only
be recommended for preterm infants ­undergoing
cardiorespiratory monitoring.
Frequency of feeds
It has been demonstrated that the occurrence of
GER can be altered by the time interval between
feeds. Omari et al. measured the occurrence of
TLESR, GER, and GE rate in preterm and term
infants with GERD, fed with different time inter-
vals between feeds (every 2, 3 and 4 h). The authors
found that gastric distension elicited by feeding
stimulated TLESRs, and that the frequency of
408 www.futuremedicine.com
feeding altered the pattern of TLESRs and the
relationship between TLESRs and acid/nonacid
GER. Specifically, when infants were fed every
4 h, the number of GER associated with a pH drop
to less than four was the highest, while the number
of GER without any pH drop was the lowest: thus,
increasing the frequency of feeds could be a useful
strategy to reduce acid GER [4] .
Milk thickening
There is no current available evidence for the use
of thickened formulas in preterm infants with
GER. The meta-analysis proposed by Horvath
et al. evaluated data from randomized, control-
led trials on the efficacy and safety of thickened
feeds for the treatment of GER in healthy term
infants. Use of thickened formulas significantly
decreased the number of episodes of regurgitation
and vomiting per day and increased weight gain
per day, whereas it had no effect on GER indexes
(acidity and number of episodes) [36] . In the study
by Wenzl et al., who evaluated the influence of
formula thickened with carob bean gum, using
pH‑MII, on GER in infants with recurrent regur-
gitations, the positive effect of thickened feeding
was found to be mainly related to a reduction
in the number of nonacid GERs and also to a
decrease of mean GER height [37] .
Corvaglia et al. evaluated using pH‑MII
whether thickening human milk (HM) with pre-
cooked starch could influence GER in preterm
infants with frequent regurgitations. During the
24-h pH‑MII recording, infants were fed alter-
nate meals of fortified HM and thickened, for-
tified HM. No differences between thickened
and nonthickened HM were found in acid and
nonacid GER indexes. The authors also analyzed
the osmolality and viscosity of thickened and non-
thickened HM: while no difference in viscosity
was documented, thickened HM had a higher
osmolality and caloric density, which probably
negatively affected GE and thus GER [38] .
Pharmacological treatment
Antireflux medications, such as prokinetics, hista-
mine 2 (H2) receptor blockers and proton-pump
inhibitors (PPIs), are commonly used in preterm
infants with the presumed diagnosis of GER,
during hospital stay in NICU and also after dis-
charge [6] . Furthermore, metoclopramide has been
reported to be one of the ten medications most
frequently prescribed in NICUs  [40] . A recent
survey conducted in four level III NICUs in the
USA, investigating use patterns of lansoprazole,
ranitidine and metoclopramide, has shown that
there is an extreme variability among centers in
future science group
 Gastroesophageal reflux disease in the neonatal intensive care unit –
the use of these three drugs, which suggests a lack
of an adequate evidence base to guide practice in
the treatment of GER in preterm infants [41] .
These data were confirmed by the online survey
conducted among a wide number of neonatolo-
gists, pediatric pulmonologists and pediatric gas-
troenterologists about their beliefs regarding the
symptoms, diagnosis, and treatment of GERD in
preterm infants in NICU, on the basis of both
clinical impression and interpretation of the lit-
erature. The survey highlighted that neonatolo-
gists were least likely to report that lansoprazole,
ranitidine and cimetidine are safe or effective,
while pulmonologists were most likely to report
that respiratory symptoms are caused by GER.
Furthermore, no pharmacological therapy had
greater than 50% of respondents supporting its
effectiveness, showing that physicians’ beliefs did
not seem to be driven by the degree of evidence in
the neonatal literature [42] .
Antacids (including
alginate-based formulations)
The major advantage of antacids is their rapid
onset of action in providing relief; however, they
usually fail to maintain a high pH level in the
presence of continued acid secretion [43] . Alginate-
based formulations act by a physical mechanism:
in the presence of gastric acid, alginates precipi-
tate to form a low-density but viscous gel, while
sodium bicarbonate contained in the formulation
is converted to carbon dioxide, which is entrapped
within the gel and contributes by forming a foam
that floats as a raft on the surface of gastric content
and can preferentially enter the esophagus ahead
of, or in lieu of, gastric content during reflux epi-
sodes [44] . Studies performed in infants on the use
of alginate-based formulations have led to con-
flicting results. Previous studies demonstrated that
these drugs reduce symptoms of GER (i.e., regur-
gitation and vomiting) in infants; Del Buono et al.
found that the drug only marginally reduced the
average reflux height, with no difference between
drug and placebo in terms of acidity and duration
of GER [45] . At present, no studies on the effect of
alginate-based ­formulations have been performed
in preterm infants.
Prokinetic drugs
Prokinetics act by modulating LES tone, intensify-
ing esophageal peristalsis and by accelerating GE;
however, despite their potential role in the treat-
ment of GER in preterm infants, the use of meto-
clopramide has been linked to possible side effects
on the extrapyramidal system, such as irritability,
dystonic reactions, drowsiness, oculogyric crisis,
future science group
Review
emesis and apnea [9] . Cisapride has been shown to
determine cardiac side effects in preterm infants,
which are further increased in infants with intra-
uterine growth retardation [46] . Domperidone is
a prokinetic antidopaminergic drug that mainly
acts outside the CNS because its molecular
weight and low lipid solubility limit its ability
to cross the blood–brain barrier. Its role in the
treatment of GER in symptomatic infants was
evaluated by Cresi et al. by pH‑MII. The authors
found no benefit in the use of domperidone, with
a paradoxical increase in the number of GER
episodes that could be the expression of a drug-
induced amplification of the motor incoordina-
tion of the neonatal gastro­esophageal tract [47] .
Similarly to cisapride, oral domperidone was
also found to increase QT interval in newborns.
Advanced gestational age and serum potassium
at the upper limit of normal were identified as
risk factors for QT‑interval prolongation [48] .
Erythromycin is a macrolide antibiotic, which
can be administered orally and intravenously,
that increases gastrointestinal motility by act-
ing directly upon motilin receptors in the GI
tract. Although the role of erythromycin in the
treatment of GER in preterm infants has never
been investigated specifically, it has been demon-
strated that oral erythromycin, administered in
intermediate or high doses as a rescue treatment,
can reduce the time to attain full enteral feed-
ing and decrease the duration of requirement
for parenteral nutrition [49] . The use of erythro-
mycin has been linked to hypertrophic pyloric
stenosis [50] , thus, this drug should also be used
with caution in preterm infants.
Gastric acid suppressants
Histamine 2-blockers
Histamine 2-blockers, such as ranitidine, work
by inhibiting the H2 receptors of the gastric
parietal cells. These drugs are widely used in
NICUs to treat preterm and term infants with
proven or presumed GER, although their effi-
cacy has not been demonstrated convincingly
in this population. Furthermore, H2 blockers
have the potential risk of counteracting a natural
defense against gastric bacterial overgrowth by
rising gastric pH.
A large cohort study, performed in over
11,000 very low birthweight infants, analyzed
data from the National Institute of Child Health
and Human Development Neonatal Research
Network on risk factors for NEC. This study
demonstrated an association between NEC and
treatment with H2 blockers [6] . Given the results
of this study, the NIH stated that “...the current
Pediatric Health (2010) 4(4) 409
REVIEW – Aceti & Corvaglia

practice of prescribing H2 blockers to prevent pharmacodynamics and systemic exposure of

or treat acid reflux in premature infants needs
to be carefully ­revaluated by all concerned” [51] .
Proton-pump inhibitors
Proton-pump inhibitors, such as omeprazole,
esomeprazole and lansoprazole, inactivate the
H+/K+ ATPase pump in parietal cells, inhibiting
gastric acid secretion and increasing intra­gastric
pH. Acid suppression therapy using PPIs is
increasingly being used to treat preterm infants
with GERD: nevertheless, the usefulness of
PPIs in decreasing GERD-associated behaviors
in infants is still questionable, and evidence
­supporting safety of PPIs is conflicting [52,53] .
Omari et al. investigated the effect of ome-
prazole 0.7 mg kg-1 day-1 on gastric acidity and
acid GER in preterm infants with reflux symp-
toms and pathological acid reflux detected by
pH monitoring. Compared to placebo, ome-
prazole significantly reduced gastric acidity,
esophageal acid exposure and number of acid
GER episodes. No acute adverse events were
reported; however, no data on long-term use
of this drug are currently available [54] . The
same authors also aimed to characterize the
esomeprazole 0.5 mg kg-1 day-1 in 26 preterm
and term infants with symptoms of GER and
pathological acid exposure. No differences
between drug and placebo were observed in the
frequency and extent of bolus reflux nor in bolus
clearance time. Acid bolus GERs and reflux
index were both reduced by esomeprazole, as
well as the number of GER symptoms recorded
[55] . Orenstein et al. evaluated the efficacy and
safety of a 4-week course of lansoprazole in
infants with symptoms suggestive of GERD
that had persisted despite a 1-week course of
nonpharmacological management. Despite no
differences in clinical outcome between drug
and placebo, a significantly higher incidence of
serious adverse events, particularly lower respi-
ratory tract infections, was ­documented in the
lansoprazole group [56] .
Conclusion
Gastroesophageal reflux diagnosis and treat-
ment still remain to be challenging issues in
NICUs, mainly due to a serious lack of evidence
in these fields. Despite that, GER is frequently
over­diagnosed and also overtreated in preterm

Executive summary
Signs & symptoms of gastroesophageal reflux
• A reflux scoring system specifically designed for preterm infants has been recently proposed: it could represent a useful tool for the
diagnosis and the management of gastroesophageal reflux disease (GERD) in preterm infants, and would limit the use of invasive
diagnostic techniques only to severe or complicated disease.
• The pathophysiological and clinical link between gastroesophageal reflux (GER) and apneas of prematurity has been hypothesized
frequently, but clinical studies aiming to demonstrate a temporal relationship between these two events have obtained
controversial results.
Diagnosis of GER
• Combined impedance and pH monitoring (pH‑MII) is being routinely used in adults, and is also emerging as the gold-standard
technique for GER detection in preterm infants.
• pH‑MII has the advantage over conventional pH monitoring to allow the detection of both acid and nonacid GER: this latter
measurement is fundamental in preterm infants, whose gastric pH is buffered for a long time after feeding.
Treatment of GER
• Approximately a-quarter of extremely low birthweight infants are given medications to treat GER: this attitude is concerning,
because recent evidence suggests an association between the use of different drugs and serious adverse effects (i.e., ranitidine and
necrotizing enterocolitis).
• A wide variability exists among neonatal intensive care units in the proportion of infants treated for presumed and/or proven GER,
suggesting a serious lack of evidence in this field.
• Conservative, nonpharmacological treatment options for GER in preterm infants, such as body positioning, are currently available and
should represent first-line treatment in infants with presumed GER.
Future perspective
• Future investigations should be oriented to clarify the relationship between GER and apnea of prematurity and to identify specific reflux
or patient characteristics that increase the risk for GER-related apneas.
• The development of clinical tools such as the questionnaire proposed by Birch et al. could be useful for the diagnosis and management of
GERD in preterm infants, and would limit use of invasive diagnostic techniques to only severe or complicated disease.
• Given the risk of severe adverse events connected with pharmacological treatment of GER in preterm infants, future research should
investigate safe and effective conservative treatment strategies for GER in this population.

410 www.futuremedicine.com future science group

 Gastroesophageal reflux disease in the neonatal intensive care unit – Review

infants. This attitude is concerning, because
recent literature suggests an asso­ciation between
the use of different drugs and serious adverse
effects in this population.
Future perspective
In our opinion, the diagnosis of GER in
NICUs would benefit by the questionnaire
proposed by Birch et al. [5] , which could limit
the use of invasive diagnostic techniques, such
as pH‑MII, only to severe or complicated dis-
ease. Furthermore, given the risk of severe
adverse events connected with pharmacological
treatment of GER in preterm infants, future
research should be oriented to investigate safe
and effective conservative treatment strategies
for GER in this population.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial
involvement with any organization or entity with a
financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript. This
includes employment, consultancies, honoraria, stock
ownership or options, expert ­testimony, grants or patents
received or ­pending, or royalties.
No writing assistance was utilized in the production
of this manuscript.

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