Acta Pædiatrica ISSN 0803–5253
VIEWPOINT ARTICLE
Focus on infantile colic
Francesco Savino (francesco.savino@unito.it)
Department of Pediatrics, Regina Margherita Children’s Hospital, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
Keywords
Dietary intervention, Gut microbiota, Infantile colic,
Lactobacillus, Treatment
Correspondence
Francesco Savino, MD PhD, Department of
Pediatrics, Regina Margherita Children’s Hospital,
University of Turin, Piazza Polonia 94, 10126 Turin,
Italy. Tel: +0039-011-3135257 |
Fax: +0039-011-677082 |
Email: francesco.savino@unito.it
Received
26 March 2007; revised 14 May 2007;
accepted 8 June 2007.
DOI:10.1111/j.1651-2227.2007.00428.x
Abstract
Infantile colic is a widespread clinical condition in the first 3 months of life, which is easily recognized,
but incompletely understood and difficult to solve. The available evidence suggests that infantile colic
might have several independent causes. The medical hypotheses include food hypersensitivity or
allergy, immaturity of gut function and dysmotility, and the behavioural hypotheses include
inadequate maternal–infant interaction, anxiety in the mother and difficult infant temperament. Other
recent hypotheses, such as hormone alterations and maternal smoking, still need confirmation,
whereas the new concept of alterations in the gut microflora, have been reported. A number of
interventions, including pharmacological agents, are discussed, but it is probable that infants with colic
require a graded strategy.
Conclusion: Considering the favourable clinical course and the wide range of manifestations, a safe approach
should be adopted, which is proportional to the intensity of the infantile colic. However, further research and
guidelines are still needed.
INTRODUCTION
Infantile colic is a widespread clinical condition in infancy,
which is observed in 10–30% of infants (1), in which a
healthy infant suffers from paroxysms of excessive, highpitched,
inconsolable crying, frequently accompanied by
flushing of the face, meteorism, drawing-up of the legs and
the passing of gas. Even though infantile colic is a common
disturbance, the aetiology is still not fully understood and
the basis of the condition remains elusive. The classical and
most often cited definition of infantile colic is based on the
rule of threes, that is, periods of crying that last for 3 h or
more per day, for 3 or more days per week and for a minimum
of 3 weeks. The condition usually resolves spontaneously by
the age of 3 months. The crying episodes tend to increase at
6 weeks of age and are most frequent in the late afternoon
and evening hours. These characteristics help to differentiate
colic from other more severe conditions (Table 1). Infantile
colic is often described as mild, moderate or severe, but
there are no set definitions for these grades. Further, colic
affects infants of all socioeconomic strata in the same way
without any evidence of family history, and there are no reported
differences in prevalence between either boys and
girls, or nursed and formula-fed infants.
Although there have been some recent progresses in understanding
infantile colic, there has been little practical
change in the clinical approach to these patients, and their
condition continues to frustrate the health care provider
and to produce parental anxiety and lack of confidence in
the infant-caring capability of the parents. Clarification of
the aetiopathogenesis and a better understanding of colic are
needed to allow a more effective and precise management
of the afflicted infant (and his/her exasperated caregiver).
This viewpoint article examines the more recent scientific
evidence supporting the various proposed organic aetiologies
of infantile colic and discusses potential new remedies
(Table 2).
LACTOSE INTOLERANCE
In recent decades, lactose intolerance due to a relative lactase
deficiency has been identified as a possible causative
factor in infant colic. The resulting failure to break down
all the lactose in the food allows significant amounts to enter
the large bowel, where it becomes a substrate for lactobacilli
and bifidobacteria in the colon. Fermentation by
these bacteria leads to production of lactic acid and hydrogen.
The rapid production of hydrogen in the lower bowel
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Table 1 Differential diagnosis between colic and clinical conditions
Common Infrequent
Feeding disorders Disaccharidase deficiency
Constipation Renal pathology, including
Anal fissures uretero-pelvic obstruction
Gastro-oesophageal Biliary tree pathology, including stones
reflux disease Acute abdomen diseases, including
Infections, including intussusception and volvulus
otitis media Incarcerated hernia
Cow’s milk protein allergy Occult fracture
Urinary tract infection Neurological abnormalities, including
Rashes, including Arnold–Chiari malformation
candidal dermatitis Ocular foreign body or abrasions or
infection
Maternal drug effect (both illicit and
prescription drugs)
Table 2 Infantile colic: aetiopathogenetic features
Lactose intolerance
Dysmotility
Gastro-oesophageal reflux
Gut hormones (motilin, ghrelin)
Gut microflora (Lactobacillus spp.)
Feeding disorders
Food hypersensitivity (cow’s milk allergy)
Psychological factors (infant–parent interaction)
distends the colon, sometimes causing pain, whereas the osmotic
pressures generated by the lactose and lactic acid in
the colon cause an influx of water, leading to further distension
of bowel.
In the first period of life, a large number of infants may display
partial malabsorption of dietary carbohydrate present
in breast milk or formulas and thus a physiological insufficiency
of gut enzyme systems may be one reason for the
development of colic. Studies measuring hydrogen in the
breath of colicky infants have produced inconsistent results,
although increases in breath hydrogen levels have been reported.
Recently, the hypothesis that colic symptoms could
be relieved by reducing the lactose content of the infant’s
feed has been tested once again in a small double-blind study
in which the feed of colicky babies was preincubated with
lactase (2). The interesting results were, however, limited by
the trial size, which prevented any formal proof of effect. In
a similar, more recent study, Kanabar et al. found a significant
difference in both crying time and breath hydrogen in
those infants who used the lactase-treated feed, supporting
the idea that symptoms could be relieved by reducing the
lactose content of a lactose-intolerant infant’s feed, but infants
whose colic is caused by other factors can expect no
relief (3).
MOTILITY
Transient dysregulation of the nervous system during development
may cause intestinal hypermotility in infants with
colic, particularly during the first few weeks of life. Radiological
studies performed many years ago stated that most
cases of infantile colic could be explained by colonic hyperperistalsis
and increased rectal pressure. There may, however,
be some bias in these studies.
Predominance of the parasympathetic as well as the sympathetic
nervous system has also been investigated. The early
literature refers to colic as ‘hypertonia of infancy’, which
was thought to be a consequence of vagotonia. This concept
is supported by the documented beneficial effects of drugs
with antispasmodic effects, such as dicyclomine hydrochloride
(4), and by the relief of high motilin levels in colicky
infants (5,6). However, whether dicyclomine exerts its effect
via the relief of intestinal spasm by a direct relaxant effect
on the colonic smooth muscle or through sedative central
nervous system effects, remains unclear. Today, the use of
this drug is limited in infants due to its known central effects
and the potential to cause respiratory depression (7). Recently,
a double-blind, placebo-controlled clinical trial was
performed to investigate the effectiveness of another drug,
cimetropium bromide (a quaternary ammonium semisynthetic
derivative of the belladonna alkaloid scopolamine), in
the treatment of infants with colic crisis (8). Thus drug acts
through the competitive antagonism of muscatine receptors
of the visceral smooth muscles and a direct myolytic activity.
This trial suggested that cimetropium bromide might significantly
decrease the duration of crying, but not the number of
crises. As far as conventional therapies are concerned, the
anticholinergic and antiadrenergic activity of some herbal
teas or drugs, such as fennel, lemon balm and camomile,
has been also proposed (9).We have already suggested that a
phytotherapeutic agent with Matricariae recrutita, Foeniculum
vulgare andMelissa officinalis improved colic in infants
through its antispasmodic and antimeteoric activity (10).
The findings of Kirjavainen et al. suggest that an imbalance
between the parasympathetic and the sympathetic nervous
system is not associated with infantile colic (11).
GASTRO-OESOPHAGEAL REFLUX (GOR)
It is appealing to explore whether there is a cause-effect relationship
between GOR and infantile colic, especially in
view of the prevalence of GOR during infancy. In my opinion,
GOR and infantile colic are two different clinical conditions.
The confusion arises when GOR does not show its
typical symptoms but is rather only characterized by excessive
crying, similar to colicky infants (12). Thus, particular
care must be taken in the differential diagnosis of these two
conditions.
Few studies have examined the role of gastric emptying
and pathological GOR in colicky infants and the conclusions
are controversial. The results suggest that, in the absence
of regurgitation and vomiting, GOR is not a common
cause of infantile irritability, and pathological GOR is only
implicated in a small subset of young infants with severe colicky
symptoms. Some clinicians suggest a defined antireflux
pharmacotherapy in these selected cases (13), but a recent
review stresses that a direct causal relationship between acid
reflux and infantile colic appears unlikely (14).
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GUT HORMONES
The gastrointestinal tract contains a wide variety of hormones
involved in the regulation of intestinal motility, and
these include vasoactive intestinal peptide (VIP), gastrin,
motilin and the newly discovered ghrelin. Lothe et al. (5)
found that VIP and gastrin levels were raised in children with
other gastrointestinal disorders, but not in infantile colic.
Further, formula-fed colicky infants had higher gastrin levels
than breastfed ones. They also reported an increased basal
motilin concentration in colicky infants. Motilin appears to
play an interesting role in the aetiopathogenesis of infantile
colic. It has been hypothesized that motilin enhances gastric
emptying, which increases small-bowel peristalsis and
decreases transit time.
More recently, it has been shown that colicky infants also
have higher serum levels of ghrelin compared to their healthy
counterparts, even though it is not clear whether the high
values observed are a cause or a consequence of infantile
colic. Ghrelin is thus thought to be implicated in promoting
abnormal hyperperistalsis and increased appetite, typical of
colicky patients. It can be considered a mediator between
gut and brain (6).
GUT MICROFLORA
Among the organic hypotheses, the role of intestinal microflora
in the aetiopathogenesis of infantile colic has been
re-proposed recently. In 1994, Lehtonen first suggested that
an aberrant gut microbial composition in the first months of
life, such as inadequate lactobacilli levels, may affect intestinal
fatty acid profiles and could thereby favour the development
of infantile colic (15). Indeed, intestinal colonization
by lactobacilli may be a prerequisite for normal mucosal immune
function.
Lactobacilli are nonpathogenic, anaerobic, Gram-positive
bacteria that play an important role in the development of
local and systemic immune responses (16), and are thus
attractive candidates for exogenous supply to infants. We
found not only lower counts of intestinal lactobacilli in colicky
infants compared to healthy ones (17), but also that
Lactobacillus brevis and L. lactis lactis might even be involved
in the pathogenesis of infantile colic by increasing
meteorism and abdominal distension. Our findings led to
the hypothesis that differences in the composition of intestinal
lactobacilli might influence the aetiopathogenesis of infantile
colic (18). An inadequate balance of lactobacilli in
colicky infants might underlie immaturity in the gut barrier
and lead to aberrant antigen transfer and immune responses,
and increased vulnerability to the breakdown of oral tolerance.
A recently published study examined the hypothesis
that modulating the intestinal microflora of colicky infants
by administering a probiotic would alleviate colic symptoms
(19). In this prospective study, a cohort of 90 breastfed colicky
infants was randomly assigned to treatment with the
probiotic Lactobacillus reuteri or simethicone. Infants in the
L. reuteri-treated-group showed significantly reduced crying
compared to the simethicone group, supporting the hypothesis
that probiotic supplementation could provide health advantages
in colic through intestinal microfloral changes and
thereby alter gut motility and/or immune responses. It has
been demonstrated that luminal endogenous flora can influence
the processes of bacteria-induced innate and adaptive
host responses through the activation of toll-like receptors
and nucleotide oligomerization domain receptors in intestinal
epithelial cells. In experimental models, cytokines can
initiate a hyper-reflex response of the enteric neuromusculature
through neuro-immune and myo-immune interactions.
Inappropriate interactions between the intestinal microflora
and toll-like receptors might affect gut motor function, leading
to abdominal dysmotility and perhaps colic symptoms.
The mechanism that L. reuteri acts through on colic symptoms
in breast-fed infants remains to be clarified.
FEEDING DIFFICULTIES
Infants with colic usually display feeding-related problems,
such as disorganized feeding behaviour, less rhythmic nutritive
and non-nutritive sucking, more discomfort following
feeding and lower responsiveness during feeding interactions.
It is possible that disorganized feeding patterns in
infants with colic are indicative of an underlying disorder in
behavioural regulation. Present knowledge underlines the
impact of these difficulties on parental and infant interactions
and suggests the potential for ongoing regulatory problems
in these infants (20). Evans et al. compared the effect
of two methods of breastfeeding (prolonged emptying of one
breast at each feed vs. both breasts equally drained at each
feed) on breast engorgement, mastitis, infantile colic and duration
of breast feeling. The former group had a lower incidence
of breast engorgement in the first week and of colic
over the first 6 months, but the majority of mothers in this
group felt it necessary to offer the second breast at the end
of a feed to satisfy their infant’s hunger (21).
FOOD HYPERSENSITIVITY
There is increased evidence that infantile colic is related to
food allergy and sometimes it is the first clinical manifestation
of atopic disease. Approximately 25% of infants with
moderate or severe symptoms have cow’s milk-dependent
colic (22,23). The immunological model of colic focuses on
possible allergens, such as cow milk proteins, in breast milk
or infant formula as the cause of the colic (24).
In a recent systematic review, Lucassen et al. confirmed
that hypoallergenic formulas were effective in the treatment
of colic in some formula-fed infants (7). Jakobsson and Lindberg
have previously reported that exclusion of cow’s milk
protein from the diet of mothers of nursed infants with colic
resulted in colic resolution. Similar efficacy was shown in
a trial using casein-hydrolyzed formula as a substitute for
cow’s milk. Lindberg (25) is also of the opinion that infants
with moderate or severe colic respond favourably to
a diet free of cow’s milk protein. More recently, Lucassen
et al. randomized Dutch infants with colic to either a wheyhydrolysate
formula or a standard formula and suggested
that substitution of cow’s milk formula by an extensively hydrolyzed
whey formula could be effective in the treatment of
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infantile colic. However, considering the favourable clinical
course of infantile colic and the fact that many but not all the
affected infants have symptoms related to cow’s milk allergy,
the majority of the studies on dietary interventions, particularly
in formula-fed infants, concluded that further research
is necessary (26). A recent trial suggests that a new formula
with partially hydrolyzed proteins, a low amount of lactose,
and the addition of a mixture of galacto-oligosaccharides
(GOS) and fructo-oligosaccharides (FOS), led to a significant
improvement in symptoms of the lower gastrointestinal
tract, such as infantile colic (27).
For colicky breastfed infants, research has shown that
simply modifying the mother’s diet could be also effective
(28). Estep et al. has even proposed that a brief intervention
with amino-acid–based formula, coupled with strict maternal
avoidance of milk and dairy products under direct supervision
of a lactation consultant, may be an effective treatment
for colic in some breast-milk-fed infants (29). This kind
of approach can, however, have a negative effect on maternal
anxiety and the duration of breast feeding, and, because
there is no doubt that human milk is superior food for all infants,
I believe that I would never suggest that human milk
be avoided at all in infants with colic (30).
PSYCHOSOCIAL FACTORS
Colic has also been suggested to be a personality disorder
in the child. Colicky infants are often considered irritable
and hypersensitive, with a ‘difficult’ temperament. However,
temperament does not provide an explanation for most of
the features of persistent infant crying, but can only be considered
a contributing factor.
It is a frequently held view that colic results from an unfavourable
climate created by inexperienced and anxious
parents, in particular mothers, and that behavioural problems
could result from a less than optimal parent–infant
interaction. The quality of infant–parent interactions is of
growing interest to those studying excessively crying and irritable
infants. In particular, the relationship between the
mothers and their persistently crying infants appeared mildly
or significantly distressed. Few studies have focused on the
role of the fathers and the whole family unit limiting our
understanding of these factors. Recently, an observational
study showed that excessive crying in infants is clearly associated
with less than optimal parental and father–infant
interaction. However, most of these problems are limited to
the severely colicky group of infants (31).
MANAGEMENT OF INFANTILE COLIC
Over the years, both behavioural to pharmacological remedies
have been studied and proposed as treatments for colic,
although few have been confirmed through rigorous scientific
evaluation in the form of randomized control trials
(RCT). Despite the favourable clinical course of infantile
colic (most infants being free from symptoms by the age of
4–5 months), many parents seek medical help. Moreover,
serious somatic problems are absent in most cases, but still
doctors and nurses believe something has to be done to assist
parents who are experiencing considerable stress.
I think the most effective treatment could be given by first
grading the colic as mild, moderate or severe, but there is no
consensus on the definition of each grade (32). The foregoing
discussion demonstrates that the management of a colicky
infant remains a frustrating problem for both carers and
paediatricians.
Behavioural interventions
The first step in treating a child with infantile colic is to
give general advice and reassurance for the parents. One
should inform them that infantile colic is a self-limiting condition
that is not due to a disease or to anything the parents
have done or omitted to do to their infants. Second, the attentiveness
of the parents should be stimulated by teaching
them to give more appropriate responses to their infants, including
less overstimulation and more effective soothing. At
the same time, the parents should be advised not to exhaust
themselves and, if possible, to leave their infants with others
(7).
Herbal formulation
Herbal teas containing mixtures of vervain, camomile, fennel,
liquorice and lemon balm have been shown to decrease
crying in infants with colic through their antispasmodic activity
(9). Products contain a variety of herbs and herbal
oil and they are thought to provide relief from flatulence
and indigestion. They are not entirely without risk, however,
as they contain sugar and alcohol. Given the multiplicity
of herbal products, the lack of standardization of strength
and dosage and the potential interference with normal feeding,
parents should be cautioned about their use for infantile
colic. A recent study showed that colic in the breastfed
infant could improve within 1 week of treatment with an
extract based on Matricariae recrutita, Foeniculum vulgare
and Melissa officinalis. The phytotherapeutic agent tested
in this study contained a high, standardized concentration
of three herbs with the added advantage of defined dosage
without the need for increased fluid intake (10).
Dietary intervention
1. Breast-fed infants. A strict cow’s milk-free diet for the
mother (with an extra supplement of calcium) may be
suggested. Recently, Hill et al. found a therapeutic benefit
in eliminating dairy products, eggs, wheat and nuts from
the diet of breast-feeding mothers while advising them
to ensure a well-balanced diet and an adequate calcium
intake (28). Dietary interventions in mothers should be
strictly monitored and continued only if they are effective.
2. Formula-fed infants. Hypoallergenic formulas, mainly extensively
hydrolysed formulas based on casein or whey,
are effective in the treatment of infantile colic (see recent
reviews by Lucassen and Garrison (7,26)). It is not
so long ago that even soy-based formulas were used in
the treatment of infantile colic. Recently, the ESPGHAN
Committee on Nutrition has recommended that soy protein
formula should not be used in infants with food al-
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lergy during the first 6 months of life, stressing that there
is no evidence supporting their use in the management of
infantile colic (33). In view of the wide range of severity
of infantile colic discussed above, and that many infants
without cow’s milk allergy have colic, extensively protein
hydrolyzed formulas might not consider the first dietary
approach. On the other hand, a new formula based on
partially hydrolysed proteins, low amounts of lactose and
supplemented with FOS and GOS was effective (27,34).
Finally, the large number of new formulas containing
functional nutrients for gut well-being indicates the need
for further research to define the best and first dietary
approach for colicky infants.
Hypertonic glucose solution
A randomized clinical trial (RCT) performed by Barr et al.
found that infants with and without colic responded to sucrose
but not to placebo. The response in the colicky infants
lasted on average <3 min whereas the infants with colic
were less effectively calmed by sucrose. In contrast, Akcam
et al. observed that 30% glucose solution might be used as
a safe, effective, easily achievable and well-tolerated alternative
method in the treatment of infantile colic and that
the placebo effect was worthy of note (35). Again, further
research is needed before this remedy can be suggested in
clinical practice.
Pharmaceutical interventions
Simethicone, a defoaming agent, has been promoted as an
effective treatment for colicky infants. It is safe and may reduce
meterorism. However, a recent meta-analysis revealed
that out of three RCTs using simethicone, only one showed
any potential benefit (7,26).
Systematic reviews of anticholinergic drugs in infantile
colic found them to be more effective than placebo. The most
commonly used agent, dicyclomine, has, however, adverse
effects and is now contraindicated in infants <6 months old
(26). Nevertheless, we have shown that cimetropium bromide
is effective in reducing crying during the colic episodes
(8)
Probiotics
Recently, a randomized, controlled study demonstrated that
Lactobacillus reuteri improved colicky symptoms in breastfed
infants more than simethicone, supporting the hypothesis
that probiotic supplementation could lead to health advantages
in colic (1,26). This is the first study performed
to evaluate the efficacy of probiotic agents for colicky infants,
and additional research, from clinical observation to
microbiologic analysis, is needed to confirm the beneficial
effects of L reuteri. Moreover, since specific probiotic strains
have specific properties and targets in the human intestinal
flora, exerting differing health benefits, it remains to be seen
whether other lactobacilli have similar effects. The mechanism
by which L. reuteri reduces colic should be the subject
of future clinical investigation to allow screening for even
more effective probiotics for colic in the future (19).
LONG-TERM OUTCOMES
Infantile colic is characterized by a favourable clinical course
and a self-limiting nature. The majority of colicky infants
completely recover by the age of 4–5 months.
With regard to allergy, an association has been observed
between colic and atopic eczema, food allergy, and respiratory
and ocular allergies (23) although one study did not
obtain such results (36).
Concerning psychological problems, Rautava et al. determined
that families that had colicky infants exhibited more
dissatisfaction with the daily functioning of their family life.
Canivet et al. performed a follow-up study of colicky infants
and controls when they reached 4 years of age and showed
that former colicky children displayed more negative emotions
and more negative moods during meals.
Our recent prospective 10-year study reported that susceptibility
to recurrent abdominal pain, allergic and psychological
disorders in childhood may be significantly increased
in subjects who suffered from infantile colic (37).
Thus, infantile colic might be an early expression of some
of the most common disorders in childhood, although other
long-term follow-up studies are still needed to confirm these
links.
CONCLUDING REMARK
There is no scientifically defined cause for infantile colic,
a behavioural clinical condition, in which an otherwise
healthy infant cries frequently and inconsolably for an extended
period of time for no discernable reason. The selflimiting
nature of colic has precluded the use of invasive investigations
to establish a pathophysiological model in vivo.
Nevertheless, there is a complex relationship between the intestinal
immune system and the commensal flora and motility,
which requires further research. As colic frequently resolves
spontaneously, dietary intervention might be more appropriate
than pharmacological treatment.
Considering the favourable clinical course of infantile
colic, the range of ways in which it manifests itself and the
day-to-day variability of crying time, a safe therapeutic approach
should be adopted and appropriate guidelines could
be useful. However, as ever, there is still a need for further
research and modification of current remedies.
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Acta Paediatr 1995; 84: 849–52.
22. Hill DJ, Hosking CS. Infantile colic and food hypersensitivity.
J Pediatr Gastroenterol Nutr 2000; 30: S67–76.
23. Kalliomaki M, Lappala P, Korvenranta H, Kero P, Isolauri E.
Extent of fussing and colic type crying preceding atopic
disease. Arch Dis Child 2001; 84: 349–50.
24. Iacono G, Carroccio A, Montalto G, Cavataio F, Bragion E,
Lorello D, et al. Severe infantile colic and food intolerance: a
long-term prospective study. J Pediatr Gastroenterol Nutr
1991; 12: 332–5.
25. Lindberg T. Infantile colic and small intestinal function: a
nutritional problem? Acta Paediatr 1999; 88: 58–60.
26. Garrison MM, Christakis DA. Early childhood: colic, child
development, and poisoning prevention. A systematic
review of treatments for infant colic. Pediatrics 2000; 106:
184–90.
27. Savino F, Palumeri E, Castagno E, Cresi F, Dalmasso P,
Cavallo F, et al. Reduction of crying episodes owing to
infantile colic: a randomized controlled study on the
efficacy of a new infant formula. Eur J Clin Nutr 2006; 60:
1304–10.
28. Hill DJ, Roy N, Heine RG, Hosking CS, Francis DE, Brown J,
et al. Effect of a low-allergen maternal diet on colic among
breastfed infants: a randomized, controlled trial. Pediatrics
2005; 116: 709–15.
29. Estep DC, Kulczycki A. Colic in breast-milk-fed infants:
treatment by temporary substitution of Neocate infant
formula. Acta Paediatr 2000; 89: 795–802.
30. Savino F, Cresi F, Silvestro L, Oggero R. Use of an amino-acid
formula in the treatment of colicky breastfed infants. Acta
Paediatr 2001; 90: 359–60.
31. Raiha H, Lehtonen L, Huhtala V, Saleva K, Korvenranta H.
Excessively crying in the family: mother-infant, father-infant
and mother-father interaction. Child Care Health Dev 2002;
28: 419–29.
32. Reijneveld SA, Brugman E, Hirasing RA. Excessive infant
crying: the impact of varying definitions. Pediatrics 2001; 108:
893–7.
33. Agostoni C, Axelsson I, Goulet O, Koletzko B, Michaelsen KF,
Puntis J, et al. Soy protein infant formulae and follow-on
formulae: a commentary by the ESPGHAN Committee on
Nutrition. J Pediatr Gastroenterol Nutr 2006; 42: 352–61.
34. Savino F, Cresi F, Maccario S, Cavallo F, Dalmasso P, Fanaro
S, et al. “Minor” feeding problems during the first months of
life: effect of a partially hydrolised milk formula containing
fructo- and galacto-oligosaccharides. Acta Paediatr 2003; 91
Suppl: 86–90.
35. Akcam M, Yilmaz A. Oral hypertonic glucose solution in the
treatment of infantile colic. Pediatrics 2006; 48: 125–7.
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Holberg CJ, Taussig LM, et al. Relation between infantile colic
and asthma/atopy: a prospective study in an unselected
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1264 C 2007 The Author/Journal Compilation C 2007 Foundation Acta Pædiatrica/Acta Pædiatrica 2007 96, pp. 1259–1264
VIEWPOINT ARTICLE
Focus on infantile colic
Francesco Savino (francesco.savino@unito.it)
Department of Pediatrics, Regina Margherita Children’s Hospital, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
Keywords
Dietary intervention, Gut microbiota, Infantile colic,
Lactobacillus, Treatment
Correspondence
Francesco Savino, MD PhD, Department of
Pediatrics, Regina Margherita Children’s Hospital,
University of Turin, Piazza Polonia 94, 10126 Turin,
Italy. Tel: +0039-011-3135257 |
Fax: +0039-011-677082 |
Email: francesco.savino@unito.it
Received
26 March 2007; revised 14 May 2007;
accepted 8 June 2007.
DOI:10.1111/j.1651-2227.2007.00428.x
Abstract
Infantile colic is a widespread clinical condition in the first 3 months of life, which is easily recognized,
but incompletely understood and difficult to solve. The available evidence suggests that infantile colic
might have several independent causes. The medical hypotheses include food hypersensitivity or
allergy, immaturity of gut function and dysmotility, and the behavioural hypotheses include
inadequate maternal–infant interaction, anxiety in the mother and difficult infant temperament. Other
recent hypotheses, such as hormone alterations and maternal smoking, still need confirmation,
whereas the new concept of alterations in the gut microflora, have been reported. A number of
interventions, including pharmacological agents, are discussed, but it is probable that infants with colic
require a graded strategy.
Conclusion: Considering the favourable clinical course and the wide range of manifestations, a safe approach
should be adopted, which is proportional to the intensity of the infantile colic. However, further research and
guidelines are still needed.
INTRODUCTION
Infantile colic is a widespread clinical condition in infancy,
which is observed in 10–30% of infants (1), in which a
healthy infant suffers from paroxysms of excessive, highpitched,
inconsolable crying, frequently accompanied by
flushing of the face, meteorism, drawing-up of the legs and
the passing of gas. Even though infantile colic is a common
disturbance, the aetiology is still not fully understood and
the basis of the condition remains elusive. The classical and
most often cited definition of infantile colic is based on the
rule of threes, that is, periods of crying that last for 3 h or
more per day, for 3 or more days per week and for a minimum
of 3 weeks. The condition usually resolves spontaneously by
the age of 3 months. The crying episodes tend to increase at
6 weeks of age and are most frequent in the late afternoon
and evening hours. These characteristics help to differentiate
colic from other more severe conditions (Table 1). Infantile
colic is often described as mild, moderate or severe, but
there are no set definitions for these grades. Further, colic
affects infants of all socioeconomic strata in the same way
without any evidence of family history, and there are no reported
differences in prevalence between either boys and
girls, or nursed and formula-fed infants.
Although there have been some recent progresses in understanding
infantile colic, there has been little practical
change in the clinical approach to these patients, and their
condition continues to frustrate the health care provider
and to produce parental anxiety and lack of confidence in
the infant-caring capability of the parents. Clarification of
the aetiopathogenesis and a better understanding of colic are
needed to allow a more effective and precise management
of the afflicted infant (and his/her exasperated caregiver).
This viewpoint article examines the more recent scientific
evidence supporting the various proposed organic aetiologies
of infantile colic and discusses potential new remedies
(Table 2).
LACTOSE INTOLERANCE
In recent decades, lactose intolerance due to a relative lactase
deficiency has been identified as a possible causative
factor in infant colic. The resulting failure to break down
all the lactose in the food allows significant amounts to enter
the large bowel, where it becomes a substrate for lactobacilli
and bifidobacteria in the colon. Fermentation by
these bacteria leads to production of lactic acid and hydrogen.
The rapid production of hydrogen in the lower bowel
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Table 1 Differential diagnosis between colic and clinical conditions
Common Infrequent
Feeding disorders Disaccharidase deficiency
Constipation Renal pathology, including
Anal fissures uretero-pelvic obstruction
Gastro-oesophageal Biliary tree pathology, including stones
reflux disease Acute abdomen diseases, including
Infections, including intussusception and volvulus
otitis media Incarcerated hernia
Cow’s milk protein allergy Occult fracture
Urinary tract infection Neurological abnormalities, including
Rashes, including Arnold–Chiari malformation
candidal dermatitis Ocular foreign body or abrasions or
infection
Maternal drug effect (both illicit and
prescription drugs)
Table 2 Infantile colic: aetiopathogenetic features
Lactose intolerance
Dysmotility
Gastro-oesophageal reflux
Gut hormones (motilin, ghrelin)
Gut microflora (Lactobacillus spp.)
Feeding disorders
Food hypersensitivity (cow’s milk allergy)
Psychological factors (infant–parent interaction)
distends the colon, sometimes causing pain, whereas the osmotic
pressures generated by the lactose and lactic acid in
the colon cause an influx of water, leading to further distension
of bowel.
In the first period of life, a large number of infants may display
partial malabsorption of dietary carbohydrate present
in breast milk or formulas and thus a physiological insufficiency
of gut enzyme systems may be one reason for the
development of colic. Studies measuring hydrogen in the
breath of colicky infants have produced inconsistent results,
although increases in breath hydrogen levels have been reported.
Recently, the hypothesis that colic symptoms could
be relieved by reducing the lactose content of the infant’s
feed has been tested once again in a small double-blind study
in which the feed of colicky babies was preincubated with
lactase (2). The interesting results were, however, limited by
the trial size, which prevented any formal proof of effect. In
a similar, more recent study, Kanabar et al. found a significant
difference in both crying time and breath hydrogen in
those infants who used the lactase-treated feed, supporting
the idea that symptoms could be relieved by reducing the
lactose content of a lactose-intolerant infant’s feed, but infants
whose colic is caused by other factors can expect no
relief (3).
MOTILITY
Transient dysregulation of the nervous system during development
may cause intestinal hypermotility in infants with
colic, particularly during the first few weeks of life. Radiological
studies performed many years ago stated that most
cases of infantile colic could be explained by colonic hyperperistalsis
and increased rectal pressure. There may, however,
be some bias in these studies.
Predominance of the parasympathetic as well as the sympathetic
nervous system has also been investigated. The early
literature refers to colic as ‘hypertonia of infancy’, which
was thought to be a consequence of vagotonia. This concept
is supported by the documented beneficial effects of drugs
with antispasmodic effects, such as dicyclomine hydrochloride
(4), and by the relief of high motilin levels in colicky
infants (5,6). However, whether dicyclomine exerts its effect
via the relief of intestinal spasm by a direct relaxant effect
on the colonic smooth muscle or through sedative central
nervous system effects, remains unclear. Today, the use of
this drug is limited in infants due to its known central effects
and the potential to cause respiratory depression (7). Recently,
a double-blind, placebo-controlled clinical trial was
performed to investigate the effectiveness of another drug,
cimetropium bromide (a quaternary ammonium semisynthetic
derivative of the belladonna alkaloid scopolamine), in
the treatment of infants with colic crisis (8). Thus drug acts
through the competitive antagonism of muscatine receptors
of the visceral smooth muscles and a direct myolytic activity.
This trial suggested that cimetropium bromide might significantly
decrease the duration of crying, but not the number of
crises. As far as conventional therapies are concerned, the
anticholinergic and antiadrenergic activity of some herbal
teas or drugs, such as fennel, lemon balm and camomile,
has been also proposed (9).We have already suggested that a
phytotherapeutic agent with Matricariae recrutita, Foeniculum
vulgare andMelissa officinalis improved colic in infants
through its antispasmodic and antimeteoric activity (10).
The findings of Kirjavainen et al. suggest that an imbalance
between the parasympathetic and the sympathetic nervous
system is not associated with infantile colic (11).
GASTRO-OESOPHAGEAL REFLUX (GOR)
It is appealing to explore whether there is a cause-effect relationship
between GOR and infantile colic, especially in
view of the prevalence of GOR during infancy. In my opinion,
GOR and infantile colic are two different clinical conditions.
The confusion arises when GOR does not show its
typical symptoms but is rather only characterized by excessive
crying, similar to colicky infants (12). Thus, particular
care must be taken in the differential diagnosis of these two
conditions.
Few studies have examined the role of gastric emptying
and pathological GOR in colicky infants and the conclusions
are controversial. The results suggest that, in the absence
of regurgitation and vomiting, GOR is not a common
cause of infantile irritability, and pathological GOR is only
implicated in a small subset of young infants with severe colicky
symptoms. Some clinicians suggest a defined antireflux
pharmacotherapy in these selected cases (13), but a recent
review stresses that a direct causal relationship between acid
reflux and infantile colic appears unlikely (14).
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GUT HORMONES
The gastrointestinal tract contains a wide variety of hormones
involved in the regulation of intestinal motility, and
these include vasoactive intestinal peptide (VIP), gastrin,
motilin and the newly discovered ghrelin. Lothe et al. (5)
found that VIP and gastrin levels were raised in children with
other gastrointestinal disorders, but not in infantile colic.
Further, formula-fed colicky infants had higher gastrin levels
than breastfed ones. They also reported an increased basal
motilin concentration in colicky infants. Motilin appears to
play an interesting role in the aetiopathogenesis of infantile
colic. It has been hypothesized that motilin enhances gastric
emptying, which increases small-bowel peristalsis and
decreases transit time.
More recently, it has been shown that colicky infants also
have higher serum levels of ghrelin compared to their healthy
counterparts, even though it is not clear whether the high
values observed are a cause or a consequence of infantile
colic. Ghrelin is thus thought to be implicated in promoting
abnormal hyperperistalsis and increased appetite, typical of
colicky patients. It can be considered a mediator between
gut and brain (6).
GUT MICROFLORA
Among the organic hypotheses, the role of intestinal microflora
in the aetiopathogenesis of infantile colic has been
re-proposed recently. In 1994, Lehtonen first suggested that
an aberrant gut microbial composition in the first months of
life, such as inadequate lactobacilli levels, may affect intestinal
fatty acid profiles and could thereby favour the development
of infantile colic (15). Indeed, intestinal colonization
by lactobacilli may be a prerequisite for normal mucosal immune
function.
Lactobacilli are nonpathogenic, anaerobic, Gram-positive
bacteria that play an important role in the development of
local and systemic immune responses (16), and are thus
attractive candidates for exogenous supply to infants. We
found not only lower counts of intestinal lactobacilli in colicky
infants compared to healthy ones (17), but also that
Lactobacillus brevis and L. lactis lactis might even be involved
in the pathogenesis of infantile colic by increasing
meteorism and abdominal distension. Our findings led to
the hypothesis that differences in the composition of intestinal
lactobacilli might influence the aetiopathogenesis of infantile
colic (18). An inadequate balance of lactobacilli in
colicky infants might underlie immaturity in the gut barrier
and lead to aberrant antigen transfer and immune responses,
and increased vulnerability to the breakdown of oral tolerance.
A recently published study examined the hypothesis
that modulating the intestinal microflora of colicky infants
by administering a probiotic would alleviate colic symptoms
(19). In this prospective study, a cohort of 90 breastfed colicky
infants was randomly assigned to treatment with the
probiotic Lactobacillus reuteri or simethicone. Infants in the
L. reuteri-treated-group showed significantly reduced crying
compared to the simethicone group, supporting the hypothesis
that probiotic supplementation could provide health advantages
in colic through intestinal microfloral changes and
thereby alter gut motility and/or immune responses. It has
been demonstrated that luminal endogenous flora can influence
the processes of bacteria-induced innate and adaptive
host responses through the activation of toll-like receptors
and nucleotide oligomerization domain receptors in intestinal
epithelial cells. In experimental models, cytokines can
initiate a hyper-reflex response of the enteric neuromusculature
through neuro-immune and myo-immune interactions.
Inappropriate interactions between the intestinal microflora
and toll-like receptors might affect gut motor function, leading
to abdominal dysmotility and perhaps colic symptoms.
The mechanism that L. reuteri acts through on colic symptoms
in breast-fed infants remains to be clarified.
FEEDING DIFFICULTIES
Infants with colic usually display feeding-related problems,
such as disorganized feeding behaviour, less rhythmic nutritive
and non-nutritive sucking, more discomfort following
feeding and lower responsiveness during feeding interactions.
It is possible that disorganized feeding patterns in
infants with colic are indicative of an underlying disorder in
behavioural regulation. Present knowledge underlines the
impact of these difficulties on parental and infant interactions
and suggests the potential for ongoing regulatory problems
in these infants (20). Evans et al. compared the effect
of two methods of breastfeeding (prolonged emptying of one
breast at each feed vs. both breasts equally drained at each
feed) on breast engorgement, mastitis, infantile colic and duration
of breast feeling. The former group had a lower incidence
of breast engorgement in the first week and of colic
over the first 6 months, but the majority of mothers in this
group felt it necessary to offer the second breast at the end
of a feed to satisfy their infant’s hunger (21).
FOOD HYPERSENSITIVITY
There is increased evidence that infantile colic is related to
food allergy and sometimes it is the first clinical manifestation
of atopic disease. Approximately 25% of infants with
moderate or severe symptoms have cow’s milk-dependent
colic (22,23). The immunological model of colic focuses on
possible allergens, such as cow milk proteins, in breast milk
or infant formula as the cause of the colic (24).
In a recent systematic review, Lucassen et al. confirmed
that hypoallergenic formulas were effective in the treatment
of colic in some formula-fed infants (7). Jakobsson and Lindberg
have previously reported that exclusion of cow’s milk
protein from the diet of mothers of nursed infants with colic
resulted in colic resolution. Similar efficacy was shown in
a trial using casein-hydrolyzed formula as a substitute for
cow’s milk. Lindberg (25) is also of the opinion that infants
with moderate or severe colic respond favourably to
a diet free of cow’s milk protein. More recently, Lucassen
et al. randomized Dutch infants with colic to either a wheyhydrolysate
formula or a standard formula and suggested
that substitution of cow’s milk formula by an extensively hydrolyzed
whey formula could be effective in the treatment of
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infantile colic. However, considering the favourable clinical
course of infantile colic and the fact that many but not all the
affected infants have symptoms related to cow’s milk allergy,
the majority of the studies on dietary interventions, particularly
in formula-fed infants, concluded that further research
is necessary (26). A recent trial suggests that a new formula
with partially hydrolyzed proteins, a low amount of lactose,
and the addition of a mixture of galacto-oligosaccharides
(GOS) and fructo-oligosaccharides (FOS), led to a significant
improvement in symptoms of the lower gastrointestinal
tract, such as infantile colic (27).
For colicky breastfed infants, research has shown that
simply modifying the mother’s diet could be also effective
(28). Estep et al. has even proposed that a brief intervention
with amino-acid–based formula, coupled with strict maternal
avoidance of milk and dairy products under direct supervision
of a lactation consultant, may be an effective treatment
for colic in some breast-milk-fed infants (29). This kind
of approach can, however, have a negative effect on maternal
anxiety and the duration of breast feeding, and, because
there is no doubt that human milk is superior food for all infants,
I believe that I would never suggest that human milk
be avoided at all in infants with colic (30).
PSYCHOSOCIAL FACTORS
Colic has also been suggested to be a personality disorder
in the child. Colicky infants are often considered irritable
and hypersensitive, with a ‘difficult’ temperament. However,
temperament does not provide an explanation for most of
the features of persistent infant crying, but can only be considered
a contributing factor.
It is a frequently held view that colic results from an unfavourable
climate created by inexperienced and anxious
parents, in particular mothers, and that behavioural problems
could result from a less than optimal parent–infant
interaction. The quality of infant–parent interactions is of
growing interest to those studying excessively crying and irritable
infants. In particular, the relationship between the
mothers and their persistently crying infants appeared mildly
or significantly distressed. Few studies have focused on the
role of the fathers and the whole family unit limiting our
understanding of these factors. Recently, an observational
study showed that excessive crying in infants is clearly associated
with less than optimal parental and father–infant
interaction. However, most of these problems are limited to
the severely colicky group of infants (31).
MANAGEMENT OF INFANTILE COLIC
Over the years, both behavioural to pharmacological remedies
have been studied and proposed as treatments for colic,
although few have been confirmed through rigorous scientific
evaluation in the form of randomized control trials
(RCT). Despite the favourable clinical course of infantile
colic (most infants being free from symptoms by the age of
4–5 months), many parents seek medical help. Moreover,
serious somatic problems are absent in most cases, but still
doctors and nurses believe something has to be done to assist
parents who are experiencing considerable stress.
I think the most effective treatment could be given by first
grading the colic as mild, moderate or severe, but there is no
consensus on the definition of each grade (32). The foregoing
discussion demonstrates that the management of a colicky
infant remains a frustrating problem for both carers and
paediatricians.
Behavioural interventions
The first step in treating a child with infantile colic is to
give general advice and reassurance for the parents. One
should inform them that infantile colic is a self-limiting condition
that is not due to a disease or to anything the parents
have done or omitted to do to their infants. Second, the attentiveness
of the parents should be stimulated by teaching
them to give more appropriate responses to their infants, including
less overstimulation and more effective soothing. At
the same time, the parents should be advised not to exhaust
themselves and, if possible, to leave their infants with others
(7).
Herbal formulation
Herbal teas containing mixtures of vervain, camomile, fennel,
liquorice and lemon balm have been shown to decrease
crying in infants with colic through their antispasmodic activity
(9). Products contain a variety of herbs and herbal
oil and they are thought to provide relief from flatulence
and indigestion. They are not entirely without risk, however,
as they contain sugar and alcohol. Given the multiplicity
of herbal products, the lack of standardization of strength
and dosage and the potential interference with normal feeding,
parents should be cautioned about their use for infantile
colic. A recent study showed that colic in the breastfed
infant could improve within 1 week of treatment with an
extract based on Matricariae recrutita, Foeniculum vulgare
and Melissa officinalis. The phytotherapeutic agent tested
in this study contained a high, standardized concentration
of three herbs with the added advantage of defined dosage
without the need for increased fluid intake (10).
Dietary intervention
1. Breast-fed infants. A strict cow’s milk-free diet for the
mother (with an extra supplement of calcium) may be
suggested. Recently, Hill et al. found a therapeutic benefit
in eliminating dairy products, eggs, wheat and nuts from
the diet of breast-feeding mothers while advising them
to ensure a well-balanced diet and an adequate calcium
intake (28). Dietary interventions in mothers should be
strictly monitored and continued only if they are effective.
2. Formula-fed infants. Hypoallergenic formulas, mainly extensively
hydrolysed formulas based on casein or whey,
are effective in the treatment of infantile colic (see recent
reviews by Lucassen and Garrison (7,26)). It is not
so long ago that even soy-based formulas were used in
the treatment of infantile colic. Recently, the ESPGHAN
Committee on Nutrition has recommended that soy protein
formula should not be used in infants with food al-
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Savino Infantile colic
lergy during the first 6 months of life, stressing that there
is no evidence supporting their use in the management of
infantile colic (33). In view of the wide range of severity
of infantile colic discussed above, and that many infants
without cow’s milk allergy have colic, extensively protein
hydrolyzed formulas might not consider the first dietary
approach. On the other hand, a new formula based on
partially hydrolysed proteins, low amounts of lactose and
supplemented with FOS and GOS was effective (27,34).
Finally, the large number of new formulas containing
functional nutrients for gut well-being indicates the need
for further research to define the best and first dietary
approach for colicky infants.
Hypertonic glucose solution
A randomized clinical trial (RCT) performed by Barr et al.
found that infants with and without colic responded to sucrose
but not to placebo. The response in the colicky infants
lasted on average <3 min whereas the infants with colic
were less effectively calmed by sucrose. In contrast, Akcam
et al. observed that 30% glucose solution might be used as
a safe, effective, easily achievable and well-tolerated alternative
method in the treatment of infantile colic and that
the placebo effect was worthy of note (35). Again, further
research is needed before this remedy can be suggested in
clinical practice.
Pharmaceutical interventions
Simethicone, a defoaming agent, has been promoted as an
effective treatment for colicky infants. It is safe and may reduce
meterorism. However, a recent meta-analysis revealed
that out of three RCTs using simethicone, only one showed
any potential benefit (7,26).
Systematic reviews of anticholinergic drugs in infantile
colic found them to be more effective than placebo. The most
commonly used agent, dicyclomine, has, however, adverse
effects and is now contraindicated in infants <6 months old
(26). Nevertheless, we have shown that cimetropium bromide
is effective in reducing crying during the colic episodes
(8)
Probiotics
Recently, a randomized, controlled study demonstrated that
Lactobacillus reuteri improved colicky symptoms in breastfed
infants more than simethicone, supporting the hypothesis
that probiotic supplementation could lead to health advantages
in colic (1,26). This is the first study performed
to evaluate the efficacy of probiotic agents for colicky infants,
and additional research, from clinical observation to
microbiologic analysis, is needed to confirm the beneficial
effects of L reuteri. Moreover, since specific probiotic strains
have specific properties and targets in the human intestinal
flora, exerting differing health benefits, it remains to be seen
whether other lactobacilli have similar effects. The mechanism
by which L. reuteri reduces colic should be the subject
of future clinical investigation to allow screening for even
more effective probiotics for colic in the future (19).
LONG-TERM OUTCOMES
Infantile colic is characterized by a favourable clinical course
and a self-limiting nature. The majority of colicky infants
completely recover by the age of 4–5 months.
With regard to allergy, an association has been observed
between colic and atopic eczema, food allergy, and respiratory
and ocular allergies (23) although one study did not
obtain such results (36).
Concerning psychological problems, Rautava et al. determined
that families that had colicky infants exhibited more
dissatisfaction with the daily functioning of their family life.
Canivet et al. performed a follow-up study of colicky infants
and controls when they reached 4 years of age and showed
that former colicky children displayed more negative emotions
and more negative moods during meals.
Our recent prospective 10-year study reported that susceptibility
to recurrent abdominal pain, allergic and psychological
disorders in childhood may be significantly increased
in subjects who suffered from infantile colic (37).
Thus, infantile colic might be an early expression of some
of the most common disorders in childhood, although other
long-term follow-up studies are still needed to confirm these
links.
CONCLUDING REMARK
There is no scientifically defined cause for infantile colic,
a behavioural clinical condition, in which an otherwise
healthy infant cries frequently and inconsolably for an extended
period of time for no discernable reason. The selflimiting
nature of colic has precluded the use of invasive investigations
to establish a pathophysiological model in vivo.
Nevertheless, there is a complex relationship between the intestinal
immune system and the commensal flora and motility,
which requires further research. As colic frequently resolves
spontaneously, dietary intervention might be more appropriate
than pharmacological treatment.
Considering the favourable clinical course of infantile
colic, the range of ways in which it manifests itself and the
day-to-day variability of crying time, a safe therapeutic approach
should be adopted and appropriate guidelines could
be useful. However, as ever, there is still a need for further
research and modification of current remedies.
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3. Kanabar D, Randhawa M, Clayton P. Improvement of
symptoms in infant colic following reduction of lactose load
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