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Dietary modifications for infantile colic (Review)
Gordon M, Biagioli E, Sorrenti M, Lingua C, Moja L, Banks SSC, Ceratto S, Savino F
Gordon M, Biagioli E, Sorrenti M, Lingua C, Moja L, Banks SSC, Ceratto S, Savino F.
Dietary modifications for infantile colic.
Cochrane Database of Systematic Reviews 2018, Issue 10. Art. No.: CD011029.
DOI: 10.1002/14651858.CD011029.pub2.
www.cochranelibrary.com
Dietary modifications for infantile colic (Review)
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TABLE OF CONTENTS
HEADER.........................................................................................................................................................................................................
ABSTRACT.....................................................................................................................................................................................................
PLAIN LANGUAGE SUMMARY.......................................................................................................................................................................
SUMMARY OF FINDINGS..............................................................................................................................................................................
BACKGROUND..............................................................................................................................................................................................
OBJECTIVES..................................................................................................................................................................................................
METHODS.....................................................................................................................................................................................................
Figure 1..................................................................................................................................................................................................
RESULTS........................................................................................................................................................................................................
Figure 2..................................................................................................................................................................................................
Figure 3..................................................................................................................................................................................................
DISCUSSION..................................................................................................................................................................................................
AUTHORS' CONCLUSIONS...........................................................................................................................................................................
ACKNOWLEDGEMENTS................................................................................................................................................................................
REFERENCES................................................................................................................................................................................................
CHARACTERISTICS OF STUDIES..................................................................................................................................................................
APPENDICES.................................................................................................................................................................................................
WHAT'S NEW.................................................................................................................................................................................................
CONTRIBUTIONS OF AUTHORS...................................................................................................................................................................
DECLARATIONS OF INTEREST.....................................................................................................................................................................
SOURCES OF SUPPORT...............................................................................................................................................................................
DIFFERENCES BETWEEN PROTOCOL AND REVIEW....................................................................................................................................
INDEX TERMS...............................................................................................................................................................................................
Dietary modifications for infantile colic (Review)
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[Intervention Review]
Dietary modifications for infantile colic
Morris Gordon1, Elena Biagioli2, Miriam Sorrenti3, Carla Lingua4, Lorenzo Moja5, Shel SC Banks6, Simone Ceratto3,7, Francesco Savino3
1School of Medicine, University of Central Lancashire, Preston, UK. 2Laboratory Methodology for Clinical Research, Istituto di Ricerche
Farmacologiche Mario Negri IRCCS, Milan, Italy. 3Department of Pediatrics, Regina Margherita Children's Hospital, Turin, Italy.
4Department of Public and Pediatric Health Sciences, University of Turin, Turin, Italy. 5Department of Biomedical Sciences for Health,
University of Milan, Milan, Switzerland. 6Department of Child Health, Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool,
UK. 7Department of Sciences of Public Health and Pediatrics, University of Turin, Regina Margherita Children's Hospital, Turin, Italy
Contact address: Francesco Savino, Department of Pediatrics, Regina Margherita Children's Hospital, P.zza Polonia 94, Turin, 10126,
Italy. francesco.savino@unito.it.
Editorial group: Cochrane Developmental, Psychosocial and Learning Problems Group.
Publication status and date: Edited (no change to conclusions), published in Issue 2, 2019.
Citation: Gordon M, Biagioli E, Sorrenti M, Lingua C, Moja L, Banks SSC, Ceratto S, Savino F. Dietary modifications for infantile colic.
Cochrane Database of Systematic Reviews 2018, Issue 10. Art. No.: CD011029. DOI: 10.1002/14651858.CD011029.pub2.
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
Infantile colic is typically defined as full-force crying for at least three hours per day, on at least three days per week, for at least three
weeks. Colic appears to be more frequent in the first six weeks of life (prevalence range of 17% to 25%), depending on the specific location
reported and definitions used, and usually resolves by three months. The aetiopathogenesis of infantile colic is unclear but most likely
multifactorial. A number of psychological, behavioural and biological components (food hypersensitivity, allergy or both; gut microflora
and dysmotility) are thought to contribute to it. The role of diet as a component in infantile colic remains controversial.
Objectives
To assess the effects of dietary modifications for reducing colic in infants less than four months of age.
Search methods
In July 2018 we searched CENTRAL, MEDLINE, Embase, 17 other databases and 2 trials registers. We also searched Google, checked
references and contacted study authors.
Selection criteria
Randomised controlled trials (RCTs) and quasi-RCTs evaluating the effects of dietary modifications, alone or in combination, for colicky
infants younger than four months of age versus another intervention or placebo. We used specific definitions for colic, age of onset and
the methods for performing the intervention. We defined 'modified diet' as any diet altered to include or exclude certain components.
Data collection and analysis
We used standard Cochrane methodological procedures. Our primary outcome was duration of crying, and secondary outcomes were
response to intervention, frequency of crying episodes, parental/family quality of life, infant sleep duration, parental satisfaction and
adverse effects.
Main results
We included 15 RCTs involving 1121 infants aged 2 to 16 weeks. All studies were small and at high risk of bias across multiple design factors
(e.g. selection, attrition). The studies covered a wide range of dietary interventions, and there was no scope for meta-analysis. Using GRADE,
we assessed the quality of the evidence as very low.
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No study reported on parental or family quality of life, infant sleep duration per 24 h, or parental satisfaction.
Low-allergen maternal diet versus a diet containing potential allergens: one study (90 infants) found that 35/47 (74%) of infants
responded (reduction in cry/fuss duration of 25%) to a low-allergen maternal diet, compared with 16/43 (37%) of infants with a maternal
diet containing potential allergens (37% difference; 95% confidence interval (CI) 18 to 56; P < 0.001).
Low-allergen diet or soy milk formula versus standard diet or cow's milk formula and dicyclomine hydrochloride: one study (120
infants) found that 10/15 (66.6%) breastfed babies responded to dicyclomine hydrochloride and a normal diet, compared with 10/16
(62.5%) on a low-allergen diet, while 24/45 (53.3%) standard formula-fed babies taking dicyclomine hydrochloride improved compared
with 29/44 (65.9%) on soy milk formula. Response was defined as a reduction of crying to less than one hour per day after 48 hours of
treatment, with remission persisting for one month.
Hydrolysed formula versus standard formula: one study (43 infants) reported that the number of infants who responded to the
intervention (cried for less than 3 hours per day on at least 3 days a week) was 8/23 in the whey hydrolysate group versus 5/20 in the
standard formula group (χ2 using yate's correction = 0.20, P = 0.65).
The same study (43 infants) reported a greater reduction in crying time postintervention with hydrolysed formula (104 min/d, 95% CI 55
to 155) than with standard formula (3 min/d, 95% CI −63 to 67); difference = 101 min/d, 95% CI 25 to 179; P = 0.02).
The author confirmed there were no adverse effects.
Hydrolysed formula or dairy- and soy-free maternal diet versus standard diet/formula and parental education or counselling: one
study (21 infants) found that crying time decreased to 2.03 h/d (SD 1.03) in the hydrolysed or dairy- and soy-free maternal diet group
compared with 1.08 h/d (SD 0.7) in the parent education or counselling group, nine days postintervention.
Partially hydrolysed, lower lactose, whey-based formulae containing oligosaccharide versus standard formula with simethicone:
one study (267 infants) found both groups experienced decreased colic episodes after seven days (partially hydrolysed formula: from 5.99
episodes (SD 1.84) to 2.47 episodes (SD 1.94); standard formula: from 5.41 episodes (SD 1.88) to 3.72 episodes (SD 1.98)); 95% CI 95% −0.7
to −1.8; P < 0.001). This difference was significant after two weeks (partially hydrolysed: 1.76 episodes (SD 1.60); standard formula: 3.32
episodes (SD 2.06); P < 0.001). The study author confirmed there were no adverse effects.
Lactase enzyme supplementation versus placebo: three studies (138 infants) assessed this comparison, but they are cross-over trials
that did not report data from before washout. There were no adverse effects in any of the studies.
Extract of Foeniculum vulgare, Matricariae recutita, and Melissa officinalis versus placebo: one study (93 infants) found that average
daily crying time was lower for infants given the extract (76.9 min/d (SD 23.5), than infants given placebo (169.9 min/d (SD 23.1) at the end
of the one-week study (95% CI −102.89 to −83.11; P < 0.01). There were no adverse effects.
Soy protein-based formula versus standard cows' milk protein-based formula: one study (19 infants) reported a mean crying time of
12.7 h/week (SD 16.4) in the soy formula group versus 17.3 h/week (SD 6.9) in the standard cows' milk group, and that 5/10 (50%) responded
in the soy formula group versus 0/9 (0%) in the standard cows' milk group.
Soy protein formula with polysaccharide versus standard soy protein formula: one cross-over study (27 infants) assessed this
comparison but did not provide disaggregated data for the pre-wash-out data.
Authors' conclusions
Currently, evidence of the effectiveness of dietary modifications for the treatment of infantile colic is sparse and at significant risk of bias.
The few available studies had small sample sizes, and most had serious limitations. There were insufficient studies, making the use of
meta-analysis unfeasable. Benefits reported for hydrolysed formulas were inconsistent.
Based on available evidence, we are unable to recommend any intervention. Future studies of single interventions, using clinically
significant outcome measures, and appropriate design and power are needed.
PLAIN LANGUAGE SUMMARY
Diet changes for infant colic
Review question
Do colicky infants show an improvement when breastfeeding mothers follow a low-allergen diet, or when formula-fed infants are fed a
special formula?
Background
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Infantile colic is a common problem afflicting otherwise healthy infants in the first three months of life. It is characterised by episodes of
inconsolable crying lasting for longer than three hours per day, for more than three days a week, for at least three weeks.
It can be very distressing for parents.
Dietary changes, such as removing cows' milk from a breastfeeding mother's diet or switching formula-fed babies to a special soy-based
formula, might reduce the symptoms of colic.
Study characteristics
We found 15 randomised controlled trials, a type of study in which participants are randomly assigned to one of two or more treatment
groups, involving a total of 1121 babies with colic. The evidence is current to July 2018.
Infants (balanced between boys and girls) were less than three months of age.
Key results
Most studies reported data on a combination of outcomes: duration of crying, number of responders in each group after treatment (i.e.
those who experienced a decrease in daily crying), or frequency of crying episodes. We present these findings below. No study reported
on parental or family quality of life, infant sleep or parental satisfaction. Six studies reported that there were no side effects as a result of
the dietary changes.
Low-allergen diet
One study (90 infants) found that more breastfed infants responded to a low-allergen maternal diet than infants on a standard diet
containing known potential allergens.
Another study (120 infants) found little difference in breastfed infants whose mothers were given a low-allergen diet (10/16, 62.5%)
and formula-fed babies who were given soy milk (29/44, 65.9%), but the researchers did find that breastfed babies responded more to
dicyclomine hydrochloride (a tablet for treating stomach spasms) than formula-fed babies.
Hydrolysed formula milk
One study (43 infants) found no clear difference in resolving symptoms of colic between the hydrolysed (hypoallergenic) and standard
cow's milk groups. They also reported a greater reduction in crying time at study end in infants who were given hydrolysed, and reported
no adverse effects.
A third study (21 infants) reported that infants whose parents were given information and support experienced a more rapid reduction in
crying time than infants who were given a hydrolysed formula or dairy- and soy-free diet (within nine days).
A fourth study (267 infants) found that both partially hydrolysed formula with oligosaccharides (carbohydrates) and a standard formula
with simethicone (a drug for treating symptoms of gas) reduced colic episodes after seven days, but effects were greater in the hydrolysed
plus oligosaccharides group after two weeks. The study author confirmed there were no adverse effects.
Lactase enzyme supplementation
Three studies (138 infants) tested the effect of adding lactase (an enzyme which helps break down the lactose (sugar) in milk) to the infants'
milk. There were no adverse effects in any of the studies.
Fennel, chamomile and lemon balm extract
One study (93 infants) found that average daily crying time in breastfed babies reduced within one week of treatment with a fennel,
chamomile and lemon balm extract. There were no adverse effects.
Soy protein-based formula
One study (19 infants) found that, compared with cows' milk formula, soy formula reduced crying time and increased the number of
responders. However, international guidance does not support the use of soy milk due to concerns that they can impact hormones in
babies, so these results are not relevant.
Quality of the evidence
Many of the studies included only small numbers of participants and were of poor quality. We did not find evidence of effectiveness for
most dietary interventions. Where studies did report some benefit, this was not large enough to be meaningful.
Conclusions
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Based on the available evidence, we are not able to recommend any of the dietary modifications assessed in this review.
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SUMMARY OF FINDINGS
Summary of findings for the main comparison. Summary of findings: dietary interventions for infantile colic versus
placebo or other interventions
Dietary interventions for infantile colic versus placebo or other interventions
Patient or population: infants with colic defined by recognised criteria
Settings: outpatient
Intervention: any dietary intervention to treat infantile colic
Comparison: placebo or any other intervention
Outcomes
Impacts
Number of studiesa
Quality of the evidence
(GRADE)
Duration of crying
This was the most commonly reported outcome, but studies
did so in an extremely heterogenous manner due to measurement tools used, as well as time and frequency of determination. There was no clear effect as regards the efficacy of any of
the agents under study for reducing the duration of crying in affected infants.
6
⊕⊝⊝⊝
Very lowb
One study reported that the number of infants crying for less
than 3 hours per day on at least 3 days a week following the intervention was 8 (out of 23) in the whey hydrolysate group versus 5 (out of 20) in the standard formula group (χ2 = 0.20, P =
0.65).
Results from 3 individual studies found that a hydrolysed formula, herbal drops and soy protein-based formula may reduce
crying time at study end (continuous outcome). 1 study found
no difference between 2 types of hydrolysed formulas.
Number of responders in each group
after treatment
There were mixed effects as regards the efficacy of the agents
under study for improving the number of responders. Results
from 2 individual studies showed that a low-allergen maternal
diet and a soy protein-based formula may increase the number of responders. However, another study found no evidence
in favour of a low-allergen diet or soy-milk formula but did find
that dicyclomine hydrochloride may increase the number of
breastfed babies who respond.
3
⊕⊝⊝⊝
Very lowb
Frequency of crying episodes per
24 h
Results from 2 individual studies showed that a hydrolysed or
dairy- and soy-free formula and a partially hydrolysed formula
may reduce the frequency of crying episodes per 24 h. As this is
very difficult to discern from normality and is not a key component of infantile colic diagnostic criteria or a necessary a goal of
clinicians, the clinical relevance of this outcome is worth readers' consideration.
2
⊕⊝⊝⊝
Very lowb
Parental or family
quality of life, including measures
of parental stress,
anxiety or depression
No data
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Infant sleep duration per 24 h at
7, 14 and 21 days
from start of intervention
No data
Parental satisfaction
No data
Adverse effects to
dietary modifications
This is a key outcome, given the population under study, which
was poorly reported in many studies. 3 studies reported that
there were no adverse effects. 3 authors (one of whom is an author on this review) of 3 other studies confirmed there were no
adverse effects. The 9 remaining studies did not report on adverse effects.
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⊕⊝⊝⊝
Very lowb
GRADE Working Group – grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change
the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to
change the estimate.
Very low quality: we are very uncertain about the estimate.
aParticipant numbers have not been included in the table as it contains multiple comparisons.
bWe downgraded the quality of the evidence for all outcomes, across all studies, due to consistent issues with incomplete outcome data,
selective reporting, the presence of extremely small sample sizes, drug and nutrition company involvement, and risk of bias. These issues
were pervasive across the evidence base and must be considered when interpreting any of the reported findings.
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BACKGROUND
The most frequently cited definition of infantile colic is the rule of
three: unexplained episodes of paroxysmal crying for longer than
three hours per day, for three days per week, for at least three
weeks (Wessel 1954). More recently, colic has been included under
functional gastrointestinal disorders (Rome IV diagnostic criteria),
and the definition has been expanded to include paroxysms of
irritability and fussiness for at least one week in an infant that has
no failure to thrive (Drossman 2016).
This condition appears to be more frequent in the first six weeks of
life, occurring in 17% to 25% of newborns, depending on geography
and definitions employed, with prevalence often peaking at that
point. It is important to note that without any intervention, colic
symptoms are usually below the threshold of such diagnostic
criteria by three months of age (Reijneveld 2001; Vandenplas 2015;
Wolke 2017).
Description of the condition
Paroxysms of inconsolable crying due to colic are often
accompanied by flushing of the face, meteorism (excessive
flatulence in the intestinal tract with distention of the abdomen),
drawing-up of the legs, and flatulence (Gupta 2007; Savino
2010). Symptoms typically start in the second week of life in
both breastfed and formula-fed infants and usually resolve by
three months of age (Lucas 1998; Vandenplas 2017). Generally
speaking, these symptoms are not indicative of disease and thus
hospital admission for these infants is generally unnecessary,
detrimental and not to be encouraged (Savino 2007). However,
most understanding of the condition is based on research that
includes a cohort of children whose parents have chosen to seek
help, so it is worth noting that this may not reflect the whole
population, and what separates colic from non-colic may simply
be the parents' decision to self-seek care (further discussions on
this point are outside of the scope of this review). Furthermore,
five per cent of colicky crying infants do have a serious underlying
medical problem (Freedman 2009; Savino 2005; Savino 2007).
Thus, clinicians should assess all colicky infants to rule out
underlying medical conditions that require investigation and
treatment (Savino 2010).
The aetiopathogenesis of infantile colic remains undefined and
is most likely multifactorial. Despite the common nature of the
condition, there is a general paucity of evidence investigating
this area. Different authors have suggested that a number
of behavioural (psychological and social) and biological (food
hypersensitivity or allergy (or both) components (Clifford 2002);
gut microflora and dysmotility) factors can contribute to its
manifestation (Camilleri 2017). These include the following.
First, lactose intolerance – due to a relative lactase deficiency
– has been postulated as a possible causative factor in infant
colic. Carbohydrate malabsorption leads to colonic fermentation
of sugars and an increase in levels of hydrogen gas. The rapid
production of hydrogen in the lower bowel distends the colon,
sometimes causing pain, whereas the osmotic pressures generated
by lactose and lactic acid in the colon cause an influx of water,
leading to further distension of the bowel. Although studies
evaluating the degree of hydrogen in the breath of colicky infants
have produced inconsistent results, some studies have reported
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increases in breath hydrogen levels (Hyams 1989; Miller 1990;
Moore 1988).
Second, the immunological model of colic focuses on possible
allergens, such as cows' milk proteins in breast milk or infant
formula, as the cause of colic. Intact proteins from the mother's
diet are hypothesised to cross over into the breast milk and
provoke an allergic response and symptoms of colic in some
infants. Consequently, some authors have proposed a low-allergen
maternal diet as a form of treatment (Hill 2005; Schach 2002).
Shannon 1921 was the first to raise the possibility that infantile
colic could be related to allergens. Since then, a number of studies
have evaluated the possible association between colic and food
hypersensitivity (Campbell 1989; Estep 2000; Forsyth 1989; Hill
1995; Hill 2005; Iacono 1991; Jakobsson 1983; Lindberg 1999; Lothe
1987; Lucassen 2000). Articles in favour of this hypothesis report
that about 25% of infants with moderate or severe symptoms might
have cows' milk protein-dependent colic (Axelsson 1986; Hill 2000;
Lindberg 1999), which improves after some days of a hypoallergenic
diet (Campbell 1989; Dupont 2010; Estep 2000; Iacono 1991; Iacono
2005; Jakobsson 1983; Jakobsson 2000; Savino 2001). For these
infants, infantile colic has been identified as the first possible
manifestation of atopic disease, and dietetic treatment should
be the first therapeutic approach (Gupta 2007; Hall 2012; Perry
2011; Savino 2010). Indeed, dietary changes, such as eliminating
cows' milk proteins, are particularly indicated in cases of suspected
intolerance to cows' milk proteins (for example, in infants with
a positive family history; atopic disease such as asthma, eczema
and other immune disorders; onset after the first month of life;
and colic associated with other gastrointestinal symptoms such as
reflux, vomiting or diarrhoea) (Hill 1995; Hill 2005; Jakobsson 1983;
Lucassen 2000).
Third, there is growing evidence that intestinal microbiota in
colicky infants differ from those in healthy controls; research has
shown higher levels of anaerobic bacteria, such as coliform and
Escherichia coli, and a lower concentration of lactobacilli, in infants
with colic (Savino 2010).
Advances in molecular technologies utilising 16S ribosomal RNA
and ribosomal DNA created the opportunity for researchers to
index the intestinal microbial composition to better understand
its association with infantile colic. The researchers found that
infants who manifested symptoms of colic were colonised with
significantly higher levels of Proteobacteria and exhibited lower
bacterial diversity when compared to their unaffected counterparts
(Dubois 2016). Additionally, colonisation levels of Actinobacteria
Bifidobacterium and Firmicute lactobacilli were inversely related to
the amount of crying and fussiness in newborns. (de Weerth 2013).
A comparison of formula-fed infants with and without
colic revealed significant differences in total bacteria,
Enterobacteriaceae and faecal ammonia (Savino 2017).
Human milk naturally contains these prebiotics, defined as
indigestible oligosaccharides, which could selectively enhance the
proliferation of certain probiotic bacteria in the colon, especially
Bifidobacterium spp (Thomas 2010). Some studies have failed to
find a protective effect of breastfeeding on the development of
colic in breastfed infants (Clifford 2002). However, it is unclear
whether these studies compared infants who were exclusively
breastfed from birth versus infants who were exclusively formulafed from birth, so it is still unclear whether breastfeeding has
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some protective effect or whether artificial feeding compromises
the infant gut microbiome in some way. Oligosaccharide prebiotics
(a mixture of oligosaccharides (0.8 g/100 mL), comprising 90%
galacto-oligosaccharides and 10% fructo-oligosaccharides), may
be effective treatments for crying in formula-fed infants with colic
(Savino 2006; Vandenplas 2017; Vivatvakin 2010).
due to concerns regarding a cross-over allergy to cows' milk protein
and their oestrogen content, such formulas should not be given
to infants with a food allergy during the first six months of life
(Agostoni 2006). As far back as 2004, the UK Chief Medical Officer
advised against administering soy protein formula to infants under
12 months of age.
More recently, researchers exploring hypotheses and rationale
for causes of infantile colic have proposed three hypothetical
mechanisms that could potentially be involved in the
aetiopathogenesis of infantile colic: immaturity of bile acid
mechanisms that alter intraluminal and absorptive mechanisms,
immaturity in motility, and alterations in the microbiome (Camilleri
2017).
Given the clinical and methodological heterogeneity of studies on
these interventions, the efficacy of these interventions in reducing
infant colic remains inconclusive at present.
Description of the intervention
Dietary modifications have often been suggested for both breastfed
and formula-fed infants with colic. We examined the following
dietary interventions.
Dietary modifications for breastfed, colicky infants who are allergic
to certain foods (cows' milk, wheat, eggs, soy, nuts, fish) involve
modifying the mother's diet to exclude these components so
the infant receives a low-allergen maternal diet. A number of
studies have demonstrated a reduction in colic when breastfeeding
mothers consumed a hypoallergenic diet (Axelsson 1986; Clyne
1991; Jakobsson 1983; Lothe 1990). For example, Hill 2005
demonstrated that a monitored, low-allergen maternal diet, which
excludes cows' milk, eggs, peanuts, tree nuts, wheat, soy and
fish, leads to a reduction in distressed behaviour. Estep 2000 also
proposed a brief interruption of breastfeeding and a temporary
substitution with an amino-acid-based formula; however, this
intervention could have negative effects on maternal-infant
interaction and on the longer term continuation of breastfeeding
and should only ever be considered as a last resort (Savino 2001;
Savino 2007; Savino 2010).
For formula-fed infants with colicky symptoms, dietary
modifications involve decreasing or removing the intake of cows'
milk from the infant's diet, or changing the type of milk formula
from starting formulas to special formulas (hypoallergenic formula,
soy milk formula, whey hydrolysed formula, casein hydrolysed
formula, amino-acid based formula, partially hydrolysed formula,
low-lactose milk formula, formula with prebiotic, etc). Some trials
have used formulas containing partially hydrolysed whey proteins,
low amounts of lactose, prebiotic oligosaccharides, and a high
beta palmitic acid content (Oggero 1994; Osborn 2013; Savino
2005; Savino 2006). In formula-fed babies, where an underlying
allergy to cows' milk protein is hypothesised to affect the infant,
extensively hydrolysed formulas, based on casein or whey, have
been shown to reduce colic symptoms (Cohen-Silver 2009; Forsyth
1989; Gupta 2007; Jakobsson 2000; Lucassen 2000). Other studies,
hypothesising that malabsorption of lactose may lead to fussing
and crying, have tested infant formulas with low-lactose content on
the basis that this may reduce excess intestinal gas (Hyams 1989;
Infante 2011; Moore 1988; Savino 2003).
Soy formulas may also reduce symptoms of colic in some
formula-fed infants. However, the European Society for
Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)
Committee on Nutrition stated recently that there is no evidence
to support the use of soy formulas for managing colic. Additionally,
How the intervention might work
Managing gut-related symptoms in infants can be challenging.
Many factors need to be taken into consideration, including
geographical, psychological, behavioural, social and family
environments, as well as the dietary approach taken to relieve
symptoms of infantile colic.
Many published studies have investigated dietary interventions
for reducing colic (Campbell 1989; Clifford 2002; Clyne 1991),
proposing a link between infant crying and the gastrointestinal
tract, thereby implicating the role of nutritional factors such
as lactose, lipids and cows' milk proteins (Feinle-Bisset 2013;
Jakobsson 1983; Jakobsson 2000; Lindberg 1999). Cows' milk whey
protein elicits symptoms of infantile colic in colicky, formula-fed
infants (Lothe 1989). Intact proteins from the mother's diet are
hypothesised to cross over into the breast milk and provoke an
allergic response and symptoms of colic in some infants (Axelsson
1986; Clyne 1991).
There are several potential pathophysiological mechanisms which
could constitute a rational basis for the therapeutic use of
dietary interventions, including immunomodulatory and antiinflammatory actions, and effects on motility and pain perception
(Drossman 2016; Gupta 2007; Hill 2000).
Different studies have proposed a possible role of nutrients in
the development of infantile colic; Nocerino 2012 investigated
potentially harmful metabolites, and Iacovou 2018 suggested
that a maternal low FODMAP (fermentable oligo-, di- and monosaccharides and polyols) diet may be associated with a reduction
of infant colic symptoms.
When exploring the causes of colic, we have to consider the
possibility that immaturity in hepatic synthesis, reduced levels
of intraluminal bile acids and impaired ileal bile absorption of
bile acids result in malabsorption of fat and other nutrients.
Alternatively, the colonic flora may be abnormal, thereby resulting
in increased nutrient fermentations with harmful metabolites, or
immaturity of the enteric nervous system might lead to abnormal
motility and sensory functions of the intestine and colon (Camilleri
2017).
The growing body of evidence of gut dysfunction support the
possible role of nutrients and gut microbiota in the development
of infantile colic due to hypersensitivity and abnormal motility
(Gupta 2007; Heine 2008; Nocerino 2012). However, the exact
mechanisms by which cows' milk and other food allergens induce
gastrointestinal motility disorders need further investigation to
understand the relationships of these symptoms to the diet
(Camilleri 2017; Farré 2013; Heine 2006). Additional factors that
could be at play include oversensitivity to stimuli, which may
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predispose some infants to irritability, fussing and increased crying
(Farré 2013; Keefe 1998; Savino 2007).
It is important to note that when all other pathologies have been
ruled out, the natural course of infantile colic is resolution; no
intervention is necessary. However, parents are often extremely
affected in a variety of ways by the symptoms of colic and seek
interventions from multiple sources. This review is clearly situated
within the context of utility for such families. Indeed, parents of
infants with symptoms of colic who do not seek attention would
not be recruited for the studies likely to be found in any review of
treatments for infantile colic.
Why it is important to do this review
A number of studies and reviews of the evidence suggest that
dietary interventions may be effective in reducing the symptoms
of colic in both breastfed and formula-fed infants (Cohen-Silver
2009; Garrison 2000; Hall 2012; Lucassen 2001; Perry 2011;
Savino 2010). Potential interventions have included a low-allergen
diet for mothers of breastfed infants (Hill 2005), hydrolysed
formulas (Forsyth 1989; Jakobsson 2000; Lucassen 2000), or lowlactose content formulas for formula-fed infants (Infante 2011;
Savino 2003; Savino 2006). This systematic review examined the
effectiveness and safety of dietary modifications for infantile colic,
where possible distinguishing between breastfed and formula-fed
infants. Although there is a relatively recent systematic review
on this topic (Iacovou 2012), the search took place in 2010 and
excluded all unpublished and grey literature. We have also used a
more recent review examining reported outcome measures within
infantile colic, Steutel 2014, to ensure that our review examines
an appropriate core outcome set (we consider this further within
the Discussion). An up-to-date systematic review using Cochrane
methodology was therefore required.
Cochrane Database of Systematic Reviews
2. Low-allergen maternal diet
3. Diet plan or dietary supplementation, regardless of duration of
intervention
Formula fed infants
1.
2.
3.
4.
5.
6.
Soy-based formula
Extensively hydrolysed formula based on whey or casein
Partially hydrolysed formula
Formula with low or no content of lactose
Amino-acid based formula
Formula that includes prebiotics
We excluded studies involving probiotics. For further information
on these interventions, please see Praveen 2014.
Types of outcome measures
Primary outcomes
1. Duration of crying* (postintervention versus baseline or
postintevention). Data could have been continuous (for
example, hours per day), or dichotomous (for example,
reduction under a predefined threshold, as determined by the
study authors). Data must have been collected prospectively,
not through retrospective recollection at the end of the study
period, using methods such as parent diaries, video or audio
recordings, or actigraphy.
Secondary outcomes
Types of participants
1. Number of responders in each group after treatment*.
Responders were defined as those who experienced a decrease
in daily crying, as reported by the study authors (dichotomous
outcome).
2. Frequency of crying episodes per 24 h* (postintervention versus
baseline) (continuous outcome)
3. Parental or family quality of life, including measures of parental
stress, anxiety or depression* (continuous outcome)
4. Infant sleep duration per 24 h at 7, 14, and 21 days*
(postintervention versus baseline) (continuous outcome)
5. Parental satisfaction*, measured by Likert scales or a numeric
rating scale (continuous outcome)
6. Adverse effects to dietary modifications: constipation*,
vomiting*, diarrhoea, apnoea, apparent life-threatening events
and lethargy (dichotomous outcome). We analysed the
frequency of all adverse effects in each study group.
Infants younger than four months of age suffering from infantile
colic (whether breastfed or formula-fed), as defined by the study.
Both breastfed and formula-fed infants were eligible.
We included outcomes evaluated after the completion of any
treatment protocol (that is, any period, any number of treatments),
and also at later follow-up, when reported.
Types of interventions
We used those outcomes indicated by an asterisk (*) to populate
the 'Summary of findings' table for the main comparison,
'dietary interventions for infantile colic versus placebo or other
interventions', where data permitted.
OBJECTIVES
To assess the effects of dietary modifications for reducing colic in
infants less than four months of age.
METHODS
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) and quasi-RCTs.
This review sought to compare any one of the following
dietary interventions, alone or in combination, versus another
intervention(s) or placebo.
Breastfed infants
1. An educational intervention that supports and directs a specific
dietary modification to modify the mother's diet by excluding
certain components such as milk, yogurt, cheese and other
foods
Search methods for identification of studies
Electronic searches
We searched the databases and trials registers listed below up
to July 2018 using the strategies in Appendix 1. We imposed no
restrictions on publication date or language.
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1. Cochrane Central Register of Controlled Trials (CENTRAL;
2018, Issue 6) in the Cochrane Library, which includes the
Cochrane Developmental, Psychosocial and Learning Problems
Specialised Register (searched 9 July 2018).
2. MEDLINE Ovid (1946 to June week 5 2018).
3. MEDLINE In-Process & Other Non-Indexed Citations Ovid
(searched 9 July 2018).
4. MEDLINE Epub Ahead of Print Ovid (searched 9 July 2018).
5. Embase Ovid (1974 to 2018 week 28).
6. CINAHL Plus EBSCOhost (Cumulative Index to Nursing and Allied
Health Literature; 1937 to 10 July 2018).
7. PsycINFO Ovid (1806 to July week 1 2018).
8. Science Citation Index Web of Science (SCI; 1970 to 10 July 2018).
9. Social Sciences Citation Index Web of Science (SSCI; 1970 to 10
July 2018).
10.Conference Proceedings Citation Index - Science Web of Science
(CPCI-S; 1990 to 10 July 2018).
11.Conference Proceedings Citation Index - Social Sciences &
Humanities Web of Science (CPCI-SS&H; 1990 to 10 July 2018).
12.Cochrane Database of Systematic Reviews (CDSR; 2018, Issue 7),
part of the Cochrane Library (searched 9 July 2018 ).
13.Database of Abstracts of Reviews of Effects (DARE; 2015, Issue
2, Final issue), part of the Cochrane Library (searched 6 January
2016).
14.LILACS (Latin American and Caribbean Health Science
Information database; search.bvsalud.org/portal/?lang=en;
searched 10 July 2018).
15.IBECS
(ibecs.isciii.es/cgi-bin/wxislind.exe/iah/online/?
IsisScript=iah/iah.xis&base=IBECS&lang=i&form=F; searched 10
July 2018).
16.HomeoIndex
(bases.bireme.br/cgi-bin/wxislind.exe/iah/
online/?IsisScript=iah/
iah.xis&base=HomeoIndex&lang=i&form=F; searched 10 July
2018).
17.Networked Digital Library of Theses and Dissertations (NDLTD;
www.ndltd.org; searched 10 July 2018).
18.TROVE (limited to Australian theses; trove.nla.gov.au; searched
10 July 2018).
19.WorldCat (limited to theses; worldcat.org; searched 10 July
2018).
20.PubMed Dietary Supplement Subset (ods.od.nih.gov/Research/
PubMed_Dietary_Supplement_Subset.aspx; searched 10 July
2018).
21.ClinicalTrials.gov (clinicaltrials.gov; searched 10 July 2018).
22.World Health Organization International Clinical Trials Registry
Platform (WHO ICTRP; apps.who.int/trialsearch; searched 10
July 2018).
Cochrane Database of Systematic Reviews
Searching other resources
We searched the bibliographies of included studies to identify any
other potentially relevant studies. On 9 July 2018, we searched
Google (www.google.com) for grey literature, using the terms
'Infantile colic AND (diet OR formula) AND randomised controlled
trial'. We handsearched conference proceedings from the ESPGHAN
annual scientific meetings from the past five years (from 2013 to
2018) to identify other potentially relevant studies that may not
be published in full. Where we identified references to relevant
unpublished or ongoing studies, we recorded them and made
attempts to obtain sufficient information so as to incorporate them
in the review. Where data were not complete, we contacted the
study authors in order to verify the eligibility of the study.
Data collection and analysis
We were unable to use all pre-planned methods, those not used
have been summarised in 'Differences between protocol and
review' section.
Selection of studies
Two reviewers (SB and MG) independently screened titles,
abstracts, and full reports for eligibility against the inclusion criteria
(see Criteria for considering studies for this review). Specifically,
they:
1. merged search results using reference management software
and removed duplicate records of the same report;
2. examined titles and abstracts to remove irrelevant reports;
3. retrieved full texts of potentially relevant reports;
4. linked together multiple reports of the same study;
5. examined full-text reports for studies that met the eligibility
criteria;
6. corresponded with investigators, when appropriate, to clarify
study eligibility;
7. at all stages, noted reasons for inclusion and exclusion of
reports, resolving any disagreements through consensus;
8. made final decisions on study inclusions and resolved any
discrepancies through a process of consensus;
9. proceeded to data collection.
As Pitkin 1999 discusses, there are issues of the accuracy with which
abstracts reflect the published report, so although we searched
conference abstracts for possible studies to include, we excluded
stand-alone abstract publications from our review; that is, we only
included abstract publications that related to a study for which we
also had a full-text report. See Differences between protocol and
review.
We recorded the outcomes of our decisions in a PRISMA diagram
(Moher 2009). See Figure 1.
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Figure 1. Study flow diagram.
Data extraction and management
We developed data extraction forms a priori, as per the
recommendations in the Cochrane Handbook for Systematic
Reviews of Interventions (Higgins 2011a). We then extracted, where
possible, information on the following.
1. Characteristics of participants: source of participants, inclusion
and exclusion criteria, total number at baseline, total number
at completion, setting, definition of 'colic' applied, diagnostic
criteria applied, type of feeding (breastfeeding, formula
feeding), age at onset of colic, age at commencement of
intervention, and potential effect modifiers such as sex.
2. Interventions and controls: number of groups, intervention(s)
applied, frequency and duration of treatment, total number of
treatments, and concomitant use of pacifier.
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3. Methods: study design, duration, sequence generation,
allocation concealment, blinding of outcome assessors, and
evaluation of success of blinding.
4. Outcomes: list of outcomes assessed, definitions used, and
values of means and standard deviations at baseline and at time
points defined by the study protocol (or change from baseline
measures, if given).
5. Results: outcome measures, follow-up data (including means
and standard deviations, standard errors, or confidence
intervals (CI) for continuous data, and summary tables for
dichotomous data), withdrawals, and losses to follow-up.
6. Other: references to other relevant studies, points to followup with study authors, comments from the study authors,
key conclusions from the study (by the study authors), other
comments from the review authors.
Two review authors (SB; MG) extracted the data independently
using the data extraction form. A third review author (FS) resolved
any persisting disagreements, which occurred on two occasions.
We collated the data in the latest version of Review Manager 5
(RevMan 5) (RevMan 2014).
Assessment of risk of bias in included studies
Using the criteria recommended in the Cochrane Handbook
for Systematic Reviews of Interventions (Higgins 2017), two
review authors (SB; MG) independently evaluated each study
for risk of bias within each of the following domains: sequence
generation; allocation concealment; blinding of parents and health
professionals; blinding of outcome assessors; incomplete outcome
data; selective outcome reporting; and other potential threats to
validity, which included consideration of potential risks due to
changing methods of data collection (such as different ways of
recording crying). They judged each domain as being at low, high,
or unclear risk of bias using the criteria described in Appendix
2, compared the judgments, and discussed and resolved any
inconsistencies in their assessments. A third review author (FS) was
available to resolve any persisting disagreements, had there been
any.
Measures of treatment effect
Dichotomous data
We were unable to conduct any meta-analyses and instead
provided narrative descriptions of the results. For planned methods
see Differences between protocol and review.
Continuous data
We were unable to conduct any meta-analyses and instead
provided narrative descriptions of the results. For planned methods
see Differences between protocol and review.
Unit of analysis issues
For each included study, we determined whether the unit of
analysis was appropriate for the unit of randomisation and the
design of that study (that is, whether the number of observations
matched the number of units that were randomised (Deeks 2017).
Cochrane Database of Systematic Reviews
Studies with multiple treatment arms
We were unable to conduct any meta-analyses and instead
provided narrative descriptions of the results. For planned methods
see Differences between protocol and review.
Cross-over studies
We were unable to conduct any meta-analyses and instead
provided narrative descriptions of the results. For planned methods
see Differences between protocol and review.
Dealing with missing data
Where data were missing, we contacted the corresponding authors
of included studies, requesting them to supply any unreported
data. Where it was not possible to obtain the missing data, we
recorded this on the data collection form, reported it in the 'Risk
of Bias' table, and discussed the extent to which the missing data
might have altered the results and, hence, the conclusions of the
review. For included studies, we noted levels of attrition.
Assessment of heterogeneity
We assessed clinical and methodological heterogeneity by
comparing the distribution of important participant characteristics
between trials (age or presence of prematurity, length of
symptoms at recruitment) and trial characteristics (randomisation,
concealment, blinding of outcome assessment, losses to follow-up,
treatment type, cointerventions).
Assessment of reporting biases
In order to minimise publication bias, we attempted to obtain the
results of any unpublished studies, to compare the results extracted
from published journal reports with the results obtained from other
sources (including any correspondence).
Data synthesis
We were unable to conduct any meta-analyses, for planned
methods see Differences between protocol and review.
Subgroup analysis and investigation of heterogeneity
We were unable to conduct any meta-analyses and thus subgroup
analyses were not possible. For planned subgroup analyses see
Differences between protocol and review.
Sensitivity analysis
We were unable to conduct any meta-analyses and thus sensitivity
analyses were not necessary. For planned methods see Differences
between protocol and review.
Summary of findings table
We assessed the overall quality of the evidence for the
following outcomes measured at postintervention using the GRADE
approach (Guyatt 2008): duration of crying; number of responders
in each group after treatment; frequency of crying episodes per 24
h; parental or family quality of life, including measures of parental
stress, anxiety or depression; infant sleep duration per 24 h at 7,
14, and 21 days; parental satisfaction; and adverse effects to dietary
modifications: constipation and vomiting. The GRADE approach
appraises the quality of evidence based on the extent to which one
can be confident that an estimate of effect, or association, reflects
the item being assessed. RCTs start as high-quality evidence, but
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may be downgraded due to: risk of bias (methodological quality),
indirectness of evidence, unexplained heterogeneity, imprecision
(sparse data), and publication bias. We determined the overall
quality of the evidence for each outcome after considering each of
these factors, and graded them as follows.
1. High quality: we are very confident that the true effect lies close
to that of the estimate of the effect.
2. Moderate quality: we are moderately confident in the effect
estimate: the true effect is likely to be close to the estimate of the
effect, but there is a possibility that it is substantially different.
3. Low quality: our confidence in the effect estimate is limited: the
true effect may be substantially different from the estimate of
the effect.
4. Very low quality: we have very little confidence in the effect
estimate: the true effect is likely to be substantially different
from the estimate of effect.
We reported our quality ratings in a 'Summary of findings' table,
which we constructed using GRADEpro GDT (GRADEpro GDT 2015),
for the comparison, 'dietary interventions for infantile colic versus
placebo or other interventions'.
RESULTS
Description of studies
See Characteristics of included studies, Characteristics of excluded
studies and Characteristics of ongoing studies.
Results of the search
Our electronic searches yielded 5486 records up to 10 July 2018; we
found two additional records from searching other sources. After
removing duplicates, two review authors independently screened
3575 titles and abstracts for relevance, excluding 3526. Of the 49
records brought forward for full-text review, we excluded 29 records
reporting on 28 studies (Characteristics of excluded studies), and
included 17 records reporting on 15 studies (Characteristics of
included studies). The three remaining reports relate to three
ongoing studies (Characteristics of ongoing studies). See Figure 1.
Included studies
This review includes 15 studies involving a total of 1121 participants
(Campbell 1989; Forsyth 1989; Hill 1995; Hill 2005; Jakobsson 2000;
Kanabar 2001; Kearney 1998; Lothe 1987; Lucassen 2000; Miller
1990; Oggero 1994; Savino 2005; Savino 2006; Taubman 1988;
Treem 1991). See Characteristics of included studies tables.
Study design
All 15 studies were RCTs, and of these, seven used a cross-over
design (Forsyth 1989; Jakobsson 2000; Kanabar 2001; Kearney
1998; Lothe 1987; Miller 1990; Treem 1991). In this review, we found
both cross-over trials that did not provide an adequate washout
period and cross-over trials that provided separate data for the first
arm.
Setting
Three studies took place in Turin, Italy (Oggero 1994; Savino
2005; Savino 2006), while two apiece were in Connecticut, USA
(Forsyth 1989; Treem 1991); Melbourne, Australia (Hill 1995; Hill
2005); and Malmö, Sweden (Jakobsson 2000; Lothe 1987). One
Cochrane Database of Systematic Reviews
study took place in Amsterdam, Netherlands (Lucassen 2000); Cork,
Ireland (Kearney 1998); London, UK (Kanabar 2001); Pennsylvania,
USA (Taubman 1988); Scotland, UK (Campbell 1989); and Sydney,
Australia (Miller 1990).
Participants were recruited from outpatient services.
Participants
The age of participants ranged from 2 weeks in Hill 2005 to 16 weeks
in Hill 1995.
Participants were diagnosed with colic on enrolment. The specific
criteria for a diagnosis of colic varied between studies, as did
the minimum length of symptoms required to make a diagnosis
of infantile colic. Most studies (87.5%) used a definition of colic
consistent with the Wessel criteria (Wessel 1954).
The studies excluded children with organic causes for their
pathology (see Characteristics of included studies tables).
Interventions
The duration of initial dietary intervention varied from 4 days in
Forsyth 1989 to 21 days in Savino 2005.
The dietary modifications included: changes to the maternal
diet (Hill 1995; Hill 2005; Oggero 1994); extensively hydrolysed
formula (Forsyth 1989; Hill 1995; Jakobsson 2000; Lucassen 2000;
Taubman 1988); a partially hydrolysed, lower lactose, whey-based
formula with oligosaccharide (Savino 2006); the use of simethicone
(Savino 2006); addition of lactase enzyme to the infant's standard
milk (Kanabar 2001; Kearney 1998; Miller 1990); phytotherapeutic
agents (Savino 2005); soy formula (Campbell 1989; Lothe 1987); or
soy formula with polysaccharide (Treem 1991).
Outcomes
Below, we present the key outcomes that studies reported, as
shown in Summary of findings for the main comparison.
1. Duration of crying (Campbell 1989; Forsyth 1989; Lucassen 2000;
Jakobsson 2000; Oggero 1994; Savino 2005).
2. Number of responders in each group after treatment (Campbell
1989; Hill 2005; Oggero 1994).
3. Frequency of crying episodes per 24 h (Taubman 1988; Savino
2006).
4. Adverse effects to dietary modifications (Kanabar 2001; Kearney
1998; Lucassen 2000; Miller 1990; Savino 2005; Savino 2006).
Funding
Four studies reported public funding and stated that there had
been no financial involvement with industry (Campbell 1989;
Jakobsson 2000; Oggero 1994; Savino 2005). The manufacturing
companies of the study intervention sponsored three studies,
but the study authors confirmed via email that industry had
no involvement in the conduct of the studies or the writing up
of the results (Lucassen 2000; Miller 1990; Savino 2006). The
manufacturers of the intervention supported eight studies in some
way (Forsyth 1989; Hill 1995; Hill 2005; Kanabar 2001; Kearney 1998;
Lothe 1987; Taubman 1988; Treem 1991).
Excluded studies
We excluded 28 studies for various reasons, as summarised below.
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1. Nine studies were not RCTs or quasi-RCTs (Arikan 2008; Bellaiche
2018; Evans 1981; Iacono 1991; Imanieh 2004; Jakobsson 1983;
Nocerino 2012; Savilahti 1989; Xinias 2017).
2. Five studies were letters in journals or narrative review articles
(Buchanan 1998; Gerrard 1984; Koonce 2011; Laws 1991;
Sargsyan 2006).
3. Eleven studies did not select participating infants who were
suffering colic before the study but included normal infants (Barr
1991; Berseth 2009; Campeotto 2011; Giovannini 2014; Iacovou
2018; Infante 2011; Rozé 2012; Savino 2003; Sherman 2015;
Vandenplas 2017; Vivatvakin 2010). As this is a review of treating
established colic, we excluded such studies.
4. Two studies were not of dietary modification, but of lactose and
cows' milk protein allergy testing in colicky babies (Liebman
1981; Pärtty 2015).
5. One study was of probiotics (Dupont 2010).
Ongoing studies
There are three ongoing studies, which are all double-blind RCTs.
Cochrane Database of Systematic Reviews
NCT01721850 is in healthy infants of 35 to 42 weeks gestational age
and 15 to 60 days old, with a Wessel diagnosis of colic (Wessel 1954).
There will be a parallel assignment with three arms: control formula
(standard formula), intervention formula one (infant formula with
hydrolysed protein (type I) and pre- and probiotics), intervention
formula two (infant formula with hydrolysed protein (type II) and
pre- and probiotics).
NCT02813772 is enrolling full-term infants with a diagnosis of "1C
according to Rome III criteria" (quote). There will be a parallel
assignment: a partially hydrolysed formula with reduced lactose
content andLactobacillus reuteri versus a standard formula.
NCT03329222 is enrolling full-term infants diagnosed with colic and
comparing a standard formula versus hydrolysed formula.
Risk of bias in included studies
Please see the 'Risk of bias' tables, beneath the Characteristics of
included studies tables, for more information of the risk of bias in
the included studies. Please also see Figure 2 and Figure 3 for a
graphic summary of the risk of bias in the included studies.
Figure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages
across all included studies.
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Figure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Allocation
Incomplete outcome data
Random sequence generation
We judged two studies to be at high risk of attrition bias because the
details of dropouts were not clear from the report, and there was
only partial information as to which group they were from (Forsyth
1989; Lothe 1987). Whilst some inference for an intention-to-treat
analysis is possible, further details were not available from the
study authors. We rated four studies at unclear risk of attrition bias
because they did not adequately describe dropouts (Jakobsson
2000; Kanabar 2001; Kearney 1998; Taubman 1988). We judged the
remaining nine studies to be at low risk of attrition bias because
dropouts were balanced across treatment groups, with similar
reasons for withdrawal and few dropouts (Campbell 1989; Hill 1995;
Hill 2005; Lucassen 2000; Miller 1990; Oggero 1994; Savino 2005;
Savino 2006; Treem 1991).
We considered nine studies to be at low risk of selection bias
based on the published report (Forsyth 1989; Jakobsson 2000;
Kanabar 2001; Kearney 1998; Oggero 1994; Savino 2005; Savino
2006; Taubman 1988; Treem 1991). In Lucassen 2000, the lead
author responded to a request for more information and confirmed
adequate sequence generation. The five remaining studies did not
describe the method of randomisation, so we judged these studies
to be at unclear risk of selection bias for this domain (Campbell
1989; Hill 1995; Hill 2005; Lothe 1987; Miller 1990).
Allocation concealment
We rated five studies at low risk of bias: four studies adequately
described allocation (Forsyth 1989; Hill 1995; Savino 2005; Savino
2006), and the lead author of one study, Lucassen 2000, responded
to a request for more information and confirmed adequate
allocation concealment. We judged the 10 remaining studies to be
at high risk of bias because the allocation concealment was not
reported (Campbell 1989; Hill 2005; Jakobsson 2000; Kanabar 2001;
Kearney 1998; Lothe 1987; Miller 1990; Oggero 1994; Taubman 1988;
Treem 1991).
Blinding
Performance bias
We rated nine studies to be at low risk of performance bias
(Campbell 1989; Hill 1995; Kanabar 2001; Kearney 1998; Lothe 1987;
Miller 1990; Lucassen 2000; Savino 2005; Treem 1991). Authors of
eight of these studies described adequate methods for blinding
participants and personnel (Campbell 1989; Hill 1995; Kanabar
2001; Kearney 1998; Lothe 1987; Miller 1990; Savino 2005; Treem
1991), while for Lucassen 2000, again the lead author responded to
a request for more information and confirmed adequate blinding of
participants and personnel. One study reported the use of blinding
but did not describe it clearly (Forsyth 1989), so we rated it at
unclear risk of performance bias. We rated five studies at high risk
of performance bias; four because they did not adequately describe
blinding of participants and personnel (Hill 2005; Jakobsson 2000;
Oggero 1994; Taubman 1988), and one, Savino 2006, because it
was impossible to blind participants owing to the nature of the
intervention and the control (simethicone had to be administered
to the infant separately).
Detection bias
We rated six studies at low risk of detection bias (Campbell 1989;
Lothe 1987; Lucassen 2000; Miller 1990; Savino 2005; Savino 2006).
Five of these studies described adequate methods for blinding
of outcome assessment (Campbell 1989; Lothe 1987; Miller 1990;
Savino 2005; Savino 2006), while the lead author of Lucassen
2000 confirmed adequate blinding by correspondence. Five studies
reported the use of blinding but did not describe it clearly, so we
judged these studies to be at unclear risk of detection bias (Forsyth
1989; Hill 1995; Kanabar 2001; Kearney 1998; Treem 1991). We rated
four studies at high risk of detection bias because they did not
describe blinding of outcome assessment adequately (Hill 2005;
Jakobsson 2000; Oggero 1994; Taubman 1988).
Selective reporting
We rated eight studies as being of high risk of reporting bias, as
the study authors did not report at all on adverse effects, did not
have a protocol or did not supply us with the information (Campbell
1989; Forsyth 1989; Hill 1995; Hill 2005; Lothe 1987; Oggero 1994;
Taubman 1988; Treem 1991). We judged the remaining seven
studies to be at low risk of reporting bias, either because it was
specifically stated in the report of the study that there were no
adverse effects (Jakobsson 2000; Kanabar 2001; Kearney 1998;
Savino 2005) or the study authors confirmed that this was the case
through correspondence (Lucassen 2000; Miller 1990; Savino 2006).
Other potential sources of bias
Because of the nature of the evidence contained within these
studies, and the claims for one product or intervention over another
in such a vulnerable population, we considered any involvement
by the companies supplying or manufacturing the intervention
product in the conduct of the studies or the writing up of results to
trigger a rating of high risk of other bias.
We considered four studies that stated no financial involvement
with industry, whether by provision of experimental product or
direct financial support for the work, to be at low risk of bias
(Campbell 1989; Jakobsson 2000; Oggero 1994; Savino 2005). We
judged a further three studies to be at unclear risk of bias as
they were sponsored by the manufacturing companies of the study
intervention, but we received confirmation that industry had no
involvement in the conduct of the studies or the writing up of the
results (Lucassen 2000; Miller 1990; Savino 2006). We rated the
remaining eight studies at high risk of bias as they stated that
they were supported in some way by the manufacturers of the
intervention or related products (Forsyth 1989; Hill 1995; Hill 2005;
Kanabar 2001; Kearney 1998; Lothe 1987; Taubman 1988; Treem
1991).
None of the studies appeared to have any other potential sources
of bias other than industry funding.
Effects of interventions
See: Summary of findings for the main comparison Summary of
findings: dietary interventions for infantile colic versus placebo or
other interventions
Below, we present the results for each combination of dietary
regimen and comparison, by assessed outcome and colic type, with
the exception of those studies for which we could not extract data.
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Despite the significant number of studies, there was no opportunity
to complete a meta-analysis due to a combination of heterogenous
outcome measures, grouping of different populations in reports
of results, and lack of reporting on key outcomes (in particular,
adverse effects) and summary outcome statistics. Thus, we provide
a narrative description of the results. We report exact P values,
where available, from the primary studies; where these were not
available, we reported the figure given. We report the GRADE rating
throughout. However, as the same two key issues affect all studies
(imprecision due to very small sample sizes and risk of bias across
all criteria), we do not make special mention of these within each
comparison. See Summary of findings for the main comparison.
1. Low-allergen maternal diet versus a diet containing known
potential allergens
Two studies (205 infants) by the same team in Australia examined
the effect of modifying breastfeeding mothers' diets to control for
proteins or other substances that might be triggering symptoms of
colic (Hill 1995; Hill 2005). However, we were unable to combine
the data from these studies in a meta-analysis because Hill 1995
grouped together breastfed babies whose mothers' diets were
modified and formula-fed babies whose own diet was modified
to remove the proteins. Authors did not report separate data for
breastfeeding mothers only, and the study authors did not respond
to our request for these data.
Primary outcome: duration of crying
Neither study reported data on this outcome (Hill 1995; Hill 2005).
Secondary outcomes: number of responders in each group after
treatment
Hill 2005 (90 infants) reported a significant difference (37%
difference; 95% CI 18 to 56; P < 0.001) in responders (i.e. reduction in
cry/fuss duration of 25%). This occurred in the low-allergen group
in 35/47 babies, compared with 16/43 babies in the control group.
The low-allergen diet excluded all dairy products, soy, wheat, eggs,
peanuts, tree nuts and fish, and included a rice milk drink, meat,
vegetables, fruit, corn and rice, as well as a calcium supplement and
rice-based bread. We rated the quality of this evidence as very low
due to risk of bias and imprecision (Summary of findings for the
main comparison).
Neither study assessed our other secondary outcomes: frequency
of crying episodes per 24 h, parental or family quality of life, infant
sleep duration per 24 h, parental satisfaction or adverse effects to
the dietary modifications.
2. Low-allergen diet or soy milk formula versus standard diet
or cow's milk formula and dicyclomine hydrochloride
Only one study (120 infants) contributed data to this comparison
(Oggero 1994). It compared a restricted, low-allergen diet in
breastfeeding mothers or soy milk in formula-fed babies versus
the addition of dicyclomine hydrochloride (a pharmacological
treatment for stomach spasms) for both breastfed and formula-fed
infants in the treatment group who also had normal diet, over a
period of 30 days.
Primary outcome: duration of crying
Authors did not specifically report duration of crying at end of
intervention.
Cochrane Database of Systematic Reviews
Secondary outcomes: number of responders in each group after
treatment
Oggero 1994 reported data on this outcome, but investigators
used stricter rules for classifying 'improvement' compared to our
protocol (Savino 2014), stating "A positive result was defined as
a reduction of crying to less than one hour per day after 48
hours of treatment, with remission persisting for one month". The
study found that 10/15 (66.6%) breastfed babies responded to
dicyclomine hydrochloride and a normal diet, compared with 10/16
(62.5%) on a low-allergen diet, while 24/45 (53.3%) formula-fed
babies on dicyclomine improved compared with 29/44 (65.9%) on
a low allergen formula.
The study did not assess our other secondary outcomes: frequency
of crying episodes per 24 h, parental or family quality of life, infant
sleep duration per 24 h, parental satisfaction or adverse effects.
3. Hydrolysed formula versus standard formula
Three studies (185 infants) compared an extensively hydrolysed
cows' milk formula with standard cows' milk formula (Forsyth 1989;
Hill 1995; Lucassen 2000). The Hill 1995 study did not separate the
results for breastfed and formula-fed infants and the study author
provided no further details in response to our request. The Forsyth
1989 study (number of infants?) used a cross-over design. However,
it was not clear from the reportwhether the results were from the
first period alone or from the first and second cross-over periods
combined, and the study authors did not respond to a request for
further information, possibly due to the age of the study. Given
this uncertainty, the Cochrane Developmental, Psychosocial and
Learning Problems editorial team advised against combining these
data in a meta-analysis, hence we provide a narrative description of
the results of this study below.
Primary outcome: duration of crying
One study (43 participants), Lucassen 2000, reported that the
number of infants crying for less than 3 hours per day on at least
3 days a week following the intervention was 8/23 in the whey
hydrolysate group versus 5/20 in the standard formula group (χ2=
0.20, P = 0.65).
The same study reported continuous data on this outcome
(Lucassen 2000), demonstrating a greater reduction in crying time
postintervention with the hydrolysed formula (104 min/d, 95% CI
55 to 155) than with the standard formula (3 min/d, 95% CI −63 to
67); difference = 101 min/d 95% CI = 25 to 179; P = 0.02). We rated
the quality of the evidence as very low (Summary of findings for the
main comparison).
Secondary outcomes: adverse effects
Lucassen 2000 did not report on adverse effects, but we received
further information from the study author indicating that there
were no adverse effects. The other two studies did not report on
adverse effects either, so it was not possible to conduct an analysis
of any adverse effects or causes of dropouts from the studies from
use of the hydrolysed formulas (Forsyth 1989; Hill 1995). We rated
the quality of the evidence as very low (Summary of findings for the
main comparison).
None of the three studies assessed our other secondary outcomes:
number of responders in each group after treatment, frequency of
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crying episodes per 24 h, parental or family quality of life, infant
sleep duration per 24 h or parental satisfaction.
4. Hydrolysed formula versus another hydrolysed formula
One study (22 infants) was designed as a cross-over trial, with each
infant receiving both types of formula for a week (Jakobsson 2000).
In this study, 10 infants were randomised to receive Alimentum
(manufactured by Abbott) and 12 infants to receive Nutramigen
(manufactured by Mead Johnson).
Primary outcome: duration of crying
The study authors concluded that both hydrolysed formulas were
equally effective in resolving symptoms for babies in the trial
who were started on standard formula. However, no separate data
from the period before the cross-over period are provided by the
authors, therefore we could not use this outcome data. We rated
the quality of this evidence as very low (Summary of findings for the
main comparison).
Secondary outcomes: adverse effects
The study authors monitored a number of possible adverse
effects, including vomiting and stool consistency. Two patients
were withdrawn from the Nutramigen group; one due to vomiting
and another due to loose stools. Stool consistency did not differ
between the two study periods; however, infants experienced a
significant increase in incidence of liquid stools from baseline only
when fed Nutramigen.
The study did not assess any of our secondary outcomes: number
of responders in each group after treatment, frequency of crying
episodes per 24 h, parental or family quality of life, infant sleep
duration per 24 h, parental satisfaction.
5. Hydrolysed formula or dairy- and soy-free maternal diet
versus standard diet/formula and parental education or
counselling
One study (21 participants) reported data on this comparison
(Taubman 1988). One group received education and training with
normal diet and thea second received no training, but either
hydrolysed formula or maternal milk-free diet.
Primary outcome: duration of crying
Taubman 1988 found that duration of crying per 24 h in the
hydrolysed or dairy- and soy-free group (N = 10) decreased to 2.03 h
(SD 1.03) by nine days into the intervention (P = 0.01). In the parent
education or counselling group (N = 10), the crying of babies per 24
h decreased to 1.08 h (SD 0.7) after nine days (P = 0.001). We rated
the quality of this evidence as very low (Summary of findings for the
main comparison).
Secondary outcomes
The study did not assess any other of our secondary outcomes:
number of responders in each group after treatment, frequency of
crying episodes per 24 hours, parental or family quality of life, infant
sleep duration per 24 h, parental satisfaction or adverse effects.
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6. Partially hydrolysed, lower lactose, whey-based formula
containing oligosaccharide versus standard formula with
simethicone
One study (267 infants) analysed the effectiveness of a
partially hydrolysed, whey-based formula containing a mixture
of oligosacharides, low lactose level, modified vegetable oil and
starch versus a standard formula (as used by parents) with
simethicone for infantile colic (Savino 2006).
Primary outcome: duration of crying time
Savino 2006 did not report data on this outcome.
Secondary outcomes
Frequency of crying episodes per 24 h
Savino 2006 found that infants (N = 130) receiving the partially
hydrolysed formula had a significant decrease (95% CI −0.7 to −1.8)
in colic episodes after one week (2.47 episodes (SD 1.94) at day
7 versus 5.99 episodes (SD 1.84) at study entry) compared with
infants (N = 137) receiving the standard formula (3.72 episodes (SD
1.98) at day 7 versus 5.41 episodes (SD 1.88) at study entry). After
two weeks, episodes of crying were significantly different (P < 0.001)
between the two groups of infants (partially hydrolysed formula:
1.76 episodes (SD 1.60) versus standard formula: 3.32 episodes (SD
2.06)). We rated the quality of the evidence as very low (Summary
of findings for the main comparison).
Adverse effects
Savino 2006 did not report data on adverse effects, but the lead
author confirmed that these were assessed and recorded as part of
the protocol, and that no infants experienced them.
The study did not report data on any of our other secondary
outcomes: number of responders in each group after treatment,
parental or family quality of life, infant sleep duration per 24 h or
parental satisfaction.
7. Lactase enzyme supplementation versus placebo
Three studies (138 participants) investigated the addition of lactase
enzyme to infant milk (Kanabar 2001; Kearney 1998; Miller 1990).
Once again, due to significant heterogeneity of outcome reporting
and limited data within the reports, as well as all three studies being
cross-over trials that did not report data from before washout, we
were unable to conduct a meta-analysis.
Primary outcome: duration of crying time
None of the three studies reported data on this outcome (Kanabar
2001; Kearney 1998; Miller 1990).
Secondary outcomes: adverse effects
Two studies reported that there were no adverse effects (Kanabar
2001; Kearney 1998), while the author of Miller 1990 confirmed via
personal correspondence that this was the case.
The study did not report on our other secondary outcomes: number
of responders in each group after treatment, frequency of crying
episodes per 24 h, parental or family quality of life, infant sleep
duration per 24 h or parental satisfaction.
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Cochrane Database of Systematic Reviews
8. Extract of Foeniculum vulgare, Matricariae recutita, and
Melissa officinalis versus placebo
Secondary outcomes: number of responders in each group after
treatment
One study (93 infants), Savino 2005, assessed the effectiveness
and side effects of a phytotherapeutic agent versus placebo, both
of which were administered twice a day for one week, in the
treatment of infantile colic. The phytotherapeutic agent was a
liquid containing extract of Foeniculum vulgare (fennel), Matricariae
recutita (camomile) and Melissa officinalis (lemon balm), with
vitamins B1, B5 and B6.
Campbell 1989 reported 0/9 responders (0%) in the control group
after therapy and 5/10 responders (50%) in the intervention group.
We rated the quality of the evidence as very low (Summary of
findings for the main comparison).
Primary outcome: duration of crying
Savino 2005 found that the average daily crying time of infants
given the phytotherapeutic agent (N = 41) was 76.9 min/d at the
end of the 1-week study (SD 23.5), compared with an average daily
crying time of 169.9 min/d (SD 23.1) in infants given placebo (N
= 47) (95% CI −102.89 to −83.11; P < 0.005). We rated the quality
of the evidence as very low (Summary of findings for the main
comparison).
The study did not assess our other secondary outcomes: frequency
of crying episodes per 24 h, parental or family quality of life, infant
sleep duration per 24 h, parental satisfaction or adverse effects.
10. Soy protein formula with polysaccharide versus standard
soy protein formula
One study (27 infants) assessed this comparison (Treem 1991).
Twelve babies received standard soy protein formula, and 15 babies
received a formula supplemented with polysaccharide. As we did
not receive a response from the study author to our request for prewashout-phase data, we are unable to analyse these results.
Secondary outcomes: adverse effects
Primary outcomes: duration of crying
Savino 2005 reported that there were no serious adverse effects.
They also reported episodes of vomiting (intervention = 8, placebo
= 2; 95% CI 0.02 to 0.28; P = 0.06) and constipation (intervention
= 4, placebo = 5; 95% CI −0.13 to 0.13; P = 0.72) for babies in the
intervention (n = 41) and placebo (n = 47) groups. We rated the
quality of this evidence as very low (Summary of findings for the
main comparison).
Treem 1991 did not report data on this outcome.
Savino 2005 did not assess any of our other secondary outcomes:
number of responders in each group after treatment, frequency of
crying episodes per 24 h, parental or family quality of life, infant
sleep duration per 24 h or parental satisfaction.
9. Soy protein-based formula versus standard cows' milk
protein-based formula
Two studies (84 infants) compared a soy protein-based formula
with standard cows' milk protein-based formula (Campbell 1989;
Lothe 1987). We were unable to conduct a meta-analysis as the
outcomes were extremely heterogeneous.
In the cross-over study (65 infants) by Lothe 1987, study authors
reported only aggregated results and did not respond to our
request for data from the first arm only. Therefore, we are unable to
consider the results any further.
Campbell 1989 (19 infants) compared duration of symptoms of colic
following a single week on either a standard casein-based cows'
milk protein formula (as control) or the same company's (Cow and
Gate) soy formula. The study was run as a cross-over with all babies
receiving both formulas over the space of two weeks. However, the
data from the first phase were not presented separately and so was
not included in this review.
Primary outcome: duration of crying
In Campbell 1989, mean crying time was lower in the soy proteinbased formula group (12.7 h/week (SD 16.4); N = 10) than in the
standard cows' milk protein-based formula group (17.3 h/week
(SD 6.9); N = 9). We rated the quality of the evidence as very low
(Summary of findings for the main comparison).
Secondary outcomes
Treem 1991 did not present pre-washout-phase data to allow us
to assess our secondary outcomes: number of responders in each
group after treatment, frequency of crying episodes per 24 h,
parental or family quality of life, infant sleep duration per 24 h,
parental satisfaction or adverse effects.
DISCUSSION
Summary of main results
This review includes 15 studies, with a total of 1121 enrolled infants,
that evaluated the effects of dietary modifications for treating
infant colic. We were not able to perform any meta-analyses due
to the heterogeneity of the studies and the outcomes that they
measured.
The studies did not routinely report adverse effects, although a
small number of study authors provided these data on request.
There were also no studies reporting data on quality of life
outcomes, which are of great interest to parents.
There is insufficient evidence to support the claims that soy
protein benefits infants with fussiness and crying, in keeping
with international guidelines (ESPGHAN) (Agostoni 2006), and that
suggested soy milk formulas should not be used (see section
Quality of the evidence below).
In sum, dietary modifications may or may not be useful or
detrimental.
Overall completeness and applicability of evidence
The results of this review rest upon trials which, in general,
were poorly designed, conducted and reported. Even though the
studies were conducted in both university clinics and primary care
hospitals in different countries, the applicability of the evidence
to clinical practice is limited. Most dietary modifications explored
by the trials, such as soy-based formula, were outdated, and
clinical outcomes and data, such as adverse effects, were limited.
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Moreover, heterogeneity was evident among definitions of colic.
Studies were most often based on a small sample from a single
centre, with no replication.
The number of infants included in the comparisons was low,
ranging from 13 for lactase drops versus placebo, to 267
for partially hydrolysed, low-lactose, modified-oil, whey-based
formula containing oligosaccharide and starch versus a standard
formula with simethicone.
The small sample sizes do not reflect the large scale of the issue
with infantile colic in our populations. In over 30 years of research
included in this review, the studies we found are not robust enough
to provide definitive answers regarding which – if any – dietary
modification works. Nor do they shed any light on what colic is,
a clearly symbiotically linked problem that also requires study.
Most research apparently concentrates on testing specific products
rather than the individual ingredients and their efficacy.
The outcome measures used are also of concern. As crying is a very
subjective concept, objective methods of recording crying would
be preferable. However, recording in diaries was the most common
method, and this is a significant weakness in the utility of the
evidence base. The use of 'treatment success' or 'responders' was
also reported in a very heterogenous manner, and many of the
specific thresholds reported bear little utility to parents or clinicians
in real-life clinical situations.
Unfortunately, the included studies did not evaluate the impact of
interventions on the quality of family life with the colicky infant.
Validated questionnaires are available for parents (Sung 2014), and,
in many ways, this is the most important set of measures for a
self-limiting problem that does not necessarily require treatment
but is treated to enhance outcomes for families. However, to date,
investigators have failed to recognise the impact that symptoms
of colic can have on parents' emotional state (Landgren 2010).
This is a very sensitive issue because this clinical situation could
damage the future parent-child relationship (Pauli-Pott 2000). In a
recent systematic review of outcome measures reported in trials
of infant colic, Steutel 2014 suggested a core set of measures that
would address such issues. As the natural history of the condition
is improvement, outcomes that measure the impact of symptoms
whilst present are, in many ways, the most relevant, and the lack of
reporting limits the applicability of the evidence.
In 2004 the UK's Chief Medical Officer, Sir Liam Donaldson, stated
that soy-based formulas should be avoided for infants because of
the "high phytoestrogen content, which could pose a risk to the
long-term reproductive health of infants" (Donaldson 2004). This
recommendation was based on "a 2003 report from the Committee
on Toxicity (COT), an independent scientific committee that advises
the Department of Health and other government agencies". It is
unlikely, therefore, that studies would now consider soy formula at
all and instead would go straight to extensively hydrolysed formula
as the dietary modification for formula-fed babies (see Forsyth
1989; Hill 1995 and Lucassen 2000 above, and to some extent
Taubman 1988 also). This limits the applicability of these earlier
studies to current practice.
Quality of the evidence
We judged the quality of the evidence on the effectiveness of
dietary modifications for infantile colic to be very low. This was
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particularly impacted by the high risk of bias in the design and
conduct of studies, and a particular concern of publication bias
linked to small study sizes, possibly associated with nutrition
company sponsorship. Additionally, sample sizes were universally
very small, with no power calculations, further downgrading
quality for imprecision.
The lack of signalled adverse effects in the studies raises serious
doubts about the quality, accountability and transparency of
these trials. In any medical research, a researcher's first priority
is to be accountable for exploring the effectiveness of different
interventions while protecting the safety of patients. It is obviously
preferable for researchers to contribute to improvements in the
safety of healthcare interventions by recording all potential adverse
effects. Collecting data on adverse effects in small children might
require additional efforts, as researchers would often need to train
caregivers to recognise and record potential adverse effects.
Given what has been said above, and the consequent low quality
of the evidence, readers should exercise caution when interpreting
the available data. Even if some results look positive (e.g. for
hydrolysed protein formulas), it is possible that the advantages
mentioned could simply be due to bias or chance. Based on the
evidence presented, we cannot recommend hydrolysed protein
formulas or other dietary modifications, and an allergen exclusion
diet is no better than standard diet or placebo.
Potential biases in the review process
We conducted comprehensive searches, including extensive
searches of the grey literature, to identify all relevant studies.
To avoid bias, two review authors (MG; SB) independently
evaluated study eligibility, extracted data, assessed risk of bias and
rated the quality of the evidence. On two occasions we resolved
initial disagreements about inclusion or exclusion with another
member of the team (FS). For the three studies in which one review
author (FS) was involved (Oggero 1994; Savino 2006; Savino 2005),
two other review authors (MG; SB) who did not participate in these
studies evaluated study eligibility, extracted data, assessed risk of
bias and rated the quality of the evidence.
As stated above, the quality of study reports in terms of detail,
clarity, study flow, outcome reporting and availability of protocols,
amongst many other factors, was variable and sporadic. In a
number of circumstances, when study authors did not respond to
our requests for further data, the reviewers had to interpret the data
to the best of their ability. This may have introduced bias into the
process.
Agreements and disagreements with other studies or
reviews
We found three earlier reviews evaluating dietary modifications for
infantile colic (Cohen-Silver 2009; Hall 2012; Perry 2011).
Cohen-Silver 2009 concluded that physicians can suggest a change
to formulas containing whey hydrolysate for formula-fed infants, as
well as maternal dietary modifications for breastfed infants. In our
view, however, the conclusions appear to over-interpret the results
of primary studies, not taking into account the poor quality of
the evidence. Although Cohen-Silver 2009 underlines that exclusive
hypoallergenic formula feeds should be reserved only for infants
with a true allergy to cows' milk protein, change to hydrolysed
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formulas cannot generally be advised to parents as routine clinical
practice.
Hall 2012 is a systematic review of studies of several nutritional
interventions such as high-fibre formula, low-allergenic formula,
lower allergenic maternal diet or the addition of lactase. Hall 2012
agreed with our review in that the quality of the research in this
field must be recognised as a priority across different independent
research groups.
Perry 2011 published a broad overview of all complementary
and alternative medicines and nutritional supplements for the
treatment of infantile colic. While we considered some of the trials
in Perry 2011, they did not focus on dietary approaches with infant
formulas or dietary modifications for breastfeeding mothers, so
their scope was very different from ours. Also, their team concluded
that there was no evidence to support clinical recommendations of
any studied dietary intervention.
AUTHORS' CONCLUSIONS
Implications for practice
Cochrane Database of Systematic Reviews
quality evidence to investigate such new milk formulas and, in
the meantime, ensure the results of this review are used to guide
current clinical practice and advice.
The implication for practice from this systematic review is that
dietary modifications can be neither recommended nor excluded
from therapies, given their unknown benefit, and that new research
must address key methodological issues, some of which are context
specific.
Implications for research
Current evidence on the effectiveness of dietary approaches for
infantile colic is based mainly on old studies, which are usually
affected by methodological limitations.
Future trials must align with clinically relevant outcomes about
which there is a consensus regarding measurement methods and
relevant time points. Reporting the resolution of colic, defined
using up-to-date criteria for diagnosis, should be mandatory.
Regarding crying time, objective measures using the host of
audiovisual and other technologies that are cheaply available,
should be considered essential to allow such assessment.
We have concluded the following.
1. It is not possible to draw any robust conclusions on the
effectiveness of dietary modifications for infantile colic because
the evidence is scant and prone to bias; presently, only a few
trials are available, most of them outdated and at serious risk of
bias.
2. Only one unreplicated study, with high risk of bias in
several areas, found that parental education or counselling
achieves a significant decrease in crying within the first three
days compared to a dairy-free maternal diet or extensively
hydrolysed formula.
3. It is not possible to draw any conclusions on the efficacy of dairyfree diets, soy-free diets, lactase enzyme supplementation of
infant milk, or the addition of soy polysaccharide to standard soy
protein formula.
4. Amongst studies examining the effect of an allergen-exclusion
diet in breastfeeding mothers, we found a significant difference
between responders in the low-allergen group versus the
control group. However, because the quality of these studies is
very poor, and the extent of the benefit observed is variable,
readers should interpret these results with caution.
5. Available data show no difference between hydrolysed and
standard infant formulas for colic; however, one study in our
review stated that the two different hydrolysed protein formulas
studied are equally effective in resolving symptoms.
6. Moreover, two different studies reported a reduction in
symptoms of infantile colic with hydrolysed formulas in
other comparisons: in the first study, a partially hydrolysed,
low-lactose, modified-oil, whey-based formula containing
oligosaccharide and starch showed a significant decrease
in colic episodes compared with standard formula with
simethicone. In the second study, hydrolysed formula relieved
symptoms of colic after soy-based formula.
7. Given these interventions are not classified as medicinal
products by regulatory bodies, there is a risk that an
interventional dietary approach can be marketed to the public
with a poor evidence base that would not occur for prescribed
medicinal products. Thus, it is important to generate high-
Other outcomes of importance to parents, such as crying time per
day, parental quality of life and sleeping time should be reported,
together with the data needed for synthesis. Adverse effects must
be reported in a manner that recognises the different forms of
such events (i.e. serious, minor and those requiring withdrawal
of therapy). Given the natural history of the condition, a major
challenge is to design trials that intervene early in the development
of colic. Alternatively, subgroups will permit consideration of
different patients based on age, for example, since a population
pre-six weeks of age is, in many ways, very different from one that
is post-six weeks of age.
More rudimentary methodological issues must also be addressed.
Power calculations based on existing primary and secondary
studies should be completed, as many of the studies we found were
underpowered and of little value. Long-term outcomes should be
considered, as this may allow economic evaluation in the future,
given that many of the interventions being studied in this review
are likely to be purchased directly by parents, and failure to address
colic can lead to extra visits with medical staff or requirement for
future medication.
Standardised tools for measuring outcomes that allow comparison
and pooling of results across studies are needed for all outcomes,
particularly given the new Rome IV criteria that refer to several
elements in defining colic that are too subjective on their own to
enable performance of sensible experimental studies (Drossman
2016). We would advise all future researchers to read this review
in detail to identify primary works that may support study design.
A recent published analysis of the existing tools being employed
underlines the need to design and validate new assessment devices
or scales for this clinical condition (García Marqués 2017), and this
analysis should consider this existing evidence base in its entirety.
As indicated above, in planning new clinical trials, researchers
should adopt a standard definition of infantile colic, such as
the definition proposed by the Rome IV Committee (Benninga
2016; Drossman 2016; Wolke 2017), which includes the following
diagnostic criteria for infantile colic: all of the following in infants
from birth to four months of age: paroxysms of irritability, fussing or
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Trusted evidence.
Informed decisions.
Better health.
crying that start and stop without obvious cause; episodes lasting
three or more hours per day and occurring at least three days per
week for at least one week; and no failure to thrive.
Given the growing evidence around the impact of infants' balance
of gut microbiota on colic and other symptoms (Dubois 2016;
Savino 2017), clear sample populations should include birth
circumstances (i.e. vaginal versus caesarean), and feeding method
(i.e. exclusive breastfeeding from birth versus exclusive formula
feeding from birth). In addition, the populations for future trials
should be separated, perhaps, into infants with a pre-existing family
history of allergy to a certain dietary component (e.g. soy or cows'
milk protein) versus those who do not.
Cochrane Database of Systematic Reviews
Many thanks to:
Margaret Anderson, Information Specialist of CDPLP, for invaluable
assistance in refining the search strategy;
Geraldine Macdonald, Co-ordinating Editor of CDPLP, for assistance
in preparing the manuscript;
Joanne Duffield, Managing Editor of CDPLP, for support and
guidance provided throughout the review process; and
Laura MacDonald, former Managing Editor of CDPLP, for support
and guidance provided throughout the development of the
protocol (Savino 2014).
We would also like to recognise the contribution of our peer
reviewers.
ACKNOWLEDGEMENTS
This review was produced within Cochrane Developmental,
Psychosocial and Learning Problems (CDPLP).
Dietary modifications for infantile colic (Review)
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
22
Cochrane
Library
Trusted evidence.
Informed decisions.
Better health.
Cochrane Database of Systematic Reviews
REFERENCES
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Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
23
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Informed decisions.
Better health.
References to studies excluded from this review
Arikan 2008 {published data only}
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Barr 1991 {published data only}
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Berseth 2009 {published data only}
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Campeotto 2011 {published data only}
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Dupont 2010 {published data only}
Dupont C, Rivero M, Grillon C, Belaroussi N, Kalindjian A,
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Evans 1981 {published data only}
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Gerrard 1984 {published data only}
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Giovannini 2014 {published data only}
Giovannini M, Verduci E, Gregori D, Ballali S, Soldi S, Ghisleni D,
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Iacono 1991 {published data only}
Iacono G, Carroccio A, Montalto G, Cavataio F, Bragion E,
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Iacovou 2018 {published data only}
Iacovou M, Mulcahy EC, Truby H, Barrett JS, Gibson PR, Muir JG.
Reducing the maternal dietary intake of indigestible and
slowly absorbed short-chain carbohydrates is associated with
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Imanieh 2004 {published data only}
Imanieh MH, Moravej H, Kashef S, Handjani F, Eghtedari F,
Kamali Sarvestani E. Cows' milk allergy in infantile colic.
Armaghane Danesh 2004;9(3):39-47. [armaghanj.yums.ac.ir/
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Infante 2011 {published data only}
Infante D, Segarra O, Luyer B. Dietary treatment of colic
caused by excess gas in infants: biochemical evidence. World
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Jakobsson 1983 {published data only}
Jakobsson I, Lindberg T. Cow's milk proteins cause infantile
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Koonce 2011 {published data only}
Koonce T, Mounsey A, Rowland K. Colicky baby? Here's a
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Laws 1991 {published data only}
Laws HF 2nd. Effect of lactase on infantile colic.
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Liebman 1981 {published data only}
Liebman WM. Infantile colic: association with lactose and milk
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Nocerino R, de Marco G, Cosenza L, Pezzella V, Passariello A,
Terrin G, et al. Efficacy of a new partially hydrolyzed whey
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Dietary modifications for infantile colic (Review)
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
24
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Better health.
Pärtty 2015 {published data only}
Pärtty A, Lehtonen L, Kalliomäki M, Salminen S,
Isolauri E. Probiotic lactobacillus rhamnosus GG therapy
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Rozé 2012 {published data only}
Rozé JC, Barbarot S, Butel MJ, Kapel N, Waligora-Dupriet AJ,
de Montgolfier I, et al. An α-lactalbumin-enriched and
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Sargsyan 2006 {published data only}
Sargsyan K, Burmucie K, Dunitz-Scheer M, Hauer AC. Effects of
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Savino 2003 {published data only}
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Vivatvakin 2010 {published data only}
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Conus NJ. Effect of a whey-predominant starter formula
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Xinias I, Analitis A, Mavroudi A, Roilides I, Lykogeorgou M,
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References to ongoing studies
NCT01721850 {unpublished data only}
NCT01721850. Evaluation of safety and efficacy of new infant
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NCT02813772 {unpublished data only}
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Iacovou M, Ralston RA, Muir J, Walker KZ, Truby H. Dietary
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References to other published versions of this review
Savino 2014
Savino F, Tarasco V, Sorrenti M, Lingua C, Moja L, Gordon M,
Biagioli E. Dietary modifications for infantile colic. Cochrane
Database of Systematic Reviews 2014, Issue 3. [DOI:
10.1002/14651858.CD011029]
* Indicates the major publication for the study
Dietary modifications for infantile colic (Review)
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Trusted evidence.
Informed decisions.
Better health.
Cochrane Database of Systematic Reviews
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Campbell 1989
Methods
Single-centre, double-blind, randomised controlled trial with 2 treatment groups
Participants
Sample size: 19 infants diagnosed with colic (0 dropped out)
Setting: recruited in a single town (Livingston, West Lothian in Scotland, UK)
Sex: 11 boys (58%), 8 girls (42%)
Mean age: 7 weeks (SD not reported, range 3 to 14)
Mean weight: not reported
Mean duration of colic (baseline): not reported
Mean crying (baseline): not reported
Feeding: formula fed (100%)
Birth order: 4 first born, 7 second born, 8 third to sixth born
Inclusion criteria: formula-fed infants with a clinical diagnosis were included in the study if they met
the Wessel 1954 criteria
Exclusion criteria: spontaneous remission in the observation week, colic not severe or already improving during baseline week. Does not specify that babies were 'otherwise well'; however, referral was via
GP or HV who considered the baby to have infant colic
Interventions
Intervention (n = 10): soy formula
Control (n = 9): standard formula
Duration: 1 week
Outcomes
Mothers asked to complete a record sheet noting the amount of time of baby's colic symptoms each
day. Record sheets scored by totaling all the periods of colic, to the nearest half hour, for 6 days of the
week, omitting the first day of the week to allow for transition from previous milk
Notes
Study start and end dates: not recorded; however it was a 2-year study period and published in 1989
COIs: none stated
Funding source: formula provided by Cow & Gate. Author was a GP, doing a research fellowship funded
by the Health Service Research Committee of Scottish Home and Health Department
Adverse effects: not reported
Comments: none
Risk of bias
Bias
Authors' judgement
Support for judgement
Random sequence generation (selection bias)
Unclear risk
Quote: "on the basis of random assignment"
Comment: no further details given. Wrote to study author but received no response
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Campbell 1989
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(Continued)
Allocation concealment
(selection bias)
High risk
Comment: no details given. Wrote to study author but received no response
Blinding of participants
and personnel (performance bias)
All outcomes
Low risk
Quote: "control and intervention were packaged in identical coded tins"
Blinding of outcome assessment (detection bias)
All outcomes
Low risk
Quote: "and the code of each pair of milks was not broken until the end of
the ... period so that the observations would be double blind"
Incomplete outcome data
(attrition bias)
All outcomes
Low risk
Comment: all data recorded. Accounted for all patients
Selective reporting (reporting bias)
High risk
Comment: no specific mention or reporting of adverse effects
Other bias
Low risk
Comment: not apparent
Forsyth 1989
Methods
Double-blind, randomised control trial with 2 treatment groups (cross-over study but we are using just
the first trial)
Participants
Sample size: 32 infants (40 referred but 8 did not satisfy eligibility criteria) diagnosed with colic enrolled (15 dropped out: 6 did not begin taking the formula, 5 did not complete the diary and 4 discontinued the study after beginning it – specific groups not described)
Setting: private practitioners and Department of Pediatrics, and Yale Child Study Center, New Haven,
Connecticut, USA
Sex: 11 boys (65%)
Mean age: 5.38 weeks (SD 1.54, range 4 to 7)
Mean weight: not reported
Mean duration of colic (baseline): not reported
Mean crying (baseline): not reported
Feeding: formula fed (100%)
Birth order: not reported
Inclusion criteria: aged 8 weeks or less at the time of enrolment, formula fed, crying reported 3 or
more h/d, parents' subjective description of colic
Exclusion criteria: any other causes of excessive crying
Interventions
Intervention (n = 9): Nutramigen casein hydrolysate
Control (n = 8): ''a cow milk formula" (quote); 1 part Enfamil (standard formula) and 2 parts Nutramigen, to ensure blinding or alternative as per cross-over trial
Duration: 4-day period and then crossed over
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Forsyth 1989
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(Continued)
Outcomes
Mothers recorded crying episodes in diaries and indicated which episodes they considered to have
been caused by colic. Crying quantified in h/d
Notes
Study start and end dates: not reported, although this paper was written in early 1989
COIs: none specifically reported; however, study funded by manufacturers of the product that was
used as the intervention
Funding source: supported by a grant from Mead Johnson, whose products were used
Adverse effects: not reported
Comments: none
Risk of bias
Bias
Authors' judgement
Support for judgement
Random sequence generation (selection bias)
Low risk
Quote: "random assignment table of random numbers"
Allocation concealment
(selection bias)
Low risk
Comment: assignment by central pharmacy
Blinding of participants
and personnel (performance bias)
All outcomes
Unclear risk
Comment: described as double-blind, but no details given and none received
from study author
Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk
Comment: described as double-blind, but no details given and none received
from study author
Incomplete outcome data
(attrition bias)
All outcomes
High risk
Comment: only partial details given on dropouts and which group they were
from. Whilst some inference can be made for an intention-to-treat analysis,
further details were not available from the study author
Selective reporting (reporting bias)
High risk
Comment: no specific mention or reporting of adverse effects. No response received from study author
Other bias
High risk
Comment: report says that cans of formula were prepared by Mead Johnson.
No further details of involvement and no response received from study author
Hill 1995
Methods
Double-blind, randomised, placebo-controlled trial over 1 week with 4 treatment groups
Participants
Sample size: 38 formula-fed and 77 breastfed infants (36 dropped out – 18 in each group)
Setting: metropolitan, community-based, well-infant centres, Melbourne, Australia
Sex: not reported
Mean age: not reported (SD not reported)
Mean weight: not reported
Mean duration of colic (baseline): 5.1 h/d (SD 3.0) intervention, 5.9 h/d (SD 3.1) control
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(Continued)
Mean crying (baseline): The mean day 1 total distress score for the intervention diet group was 330.5
minutes, and for the control diet group, 268.0 minutes (P = 0.12)
Feeding: formula fed (33%; n = 38)
Inclusion criteria: aged 4-16 weeks, uncomplicated pregnancy of more than 37 weeks' duration, uneventful perinatal period, colic definition 'rule of three', and otherwise healthy except for colic. Also included those on medication for colic, as long as medications continued throughout the trial
Exclusion criteria: not reported
Interventions
Intervention (n = 54): mothers of breastfed babies given a hypoallergenic or anti-oligogenic diet (excluding food dyes, additives, preservatives, milk, egg, wheat or nuts), and formula-fed babies provided
with a casein based hydrolysate formula (Pregestamil)
Control (n = 61): mothers of breastfed babies given a standard oligoantigenic diet (avoiding food dyes,
additives, preservatives), and formula-fed babies given standard formula (Enfamil Reduced Iron)
Duration: 1 week
Outcomes
Parents instructed in the use of a 24-h distress score chart, which they were asked to complete on day 1
and day 8 of the trial, with distress marked in min/h
Notes
Study start and end dates: not reported; however, paper does report that the original study was intended to be 12 months, but that it was harder to recruit than they had expected and the study was finally closed after 3 years
COIs: none reported
Funding source: supported by a grant from Mead Johnson
Adverse effects: none reported
Comments: none
Risk of bias
Bias
Authors' judgement
Support for judgement
Random sequence generation (selection bias)
Unclear risk
Comment: says it is randomised. Wrote to study author but received no response
Allocation concealment
(selection bias)
Low risk
Comment: sealed envelopes for assignment
Blinding of participants
and personnel (performance bias)
All outcomes
Low risk
Comment: double-blind – identical sealed tins
Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk
Comment: as above
Incomplete outcome data
(attrition bias)
All outcomes
Low risk
Comment: all patient outcomes described
Selective reporting (reporting bias)
High risk
Comment: no specific mention or reporting of adverse effects. No response received from study author
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Hill 1995
Trusted evidence.
Informed decisions.
Better health.
Cochrane Database of Systematic Reviews
(Continued)
Other bias
High risk
Comment: supported by a grant from Mead Johnson. No further details of involvement and no response received from study author
Hill 2005
Methods
Randomised controlled trial with 2 treatment groups
Participants
Sample size: 107 infants (17 dropped out – intervention = 6, control = 11)
Setting: metropolitan, community-based, well-infant centres, Melbourne, Australia
Sex: 54 boys (50%) 53 girls (50%)
Mean age: 5.7 weeks (SD 1.1, range 2.9 to 8.6)
Mean weight: not reported
Mean duration of colic (baseline): Mean distress duration at start of diet, in weeks intervention = 3.2
(range = 1 to 7), control = 3.4 (range = 1 to 6.0)
Mean crying (baseline): not reported
Feeding: breastfed (100%)
Birth order: not reported
Inclusion criteria: < 6 weeks of age, breastfed, well-term infants (gestational age of > 37 weeks), normal singleton pregnancy, otherwise uneventful perinatal history and no perinatal morbidity other than
distress, and presence of 'rule of three' crying in the week before presentation
Exclusion criteria: mothers who were vegan, babies who were formula fed, spontaneous improvement
Interventions
Intervention (n = 47): low-allergen diet without milk, soy, nuts, eggs, wheat and soy, but including a
rice drink every day and rice bread
Control (n = 43): diet must have included milk, peanuts, egg, wheat, fish, tree nuts and soy every day
Duration: 1 week
Outcomes
Detailed food diary by mothers, and recording of infant crying or fussing behaviour on a pre-validated
chart, for 48 h on days 1, 2, 8 and 9
Notes
Study start and end dates: 2000 (start) to 2002 (end)
COIs: not reported but see funding source directly below
Funding source: financed by the Rice Growers' Co-operative, Australia. Intervention was rice milk and
rice bread
Adverse effects: none reported
Comments: none
Risk of bias
Bias
Authors' judgement
Support for judgement
Random sequence generation (selection bias)
Unclear risk
Quote: "referred to the Department of Allergy for diet randomisation"
Quote: "assigned to one of the diets by the research dietician on the basis of a
randomisation schedule provided by the statistician"
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(Continued)
Comment: no further details. Wrote to study author but received no response
Allocation concealment
(selection bias)
High risk
Comment: no details. Wrote to study author but received no response
Blinding of participants
and personnel (performance bias)
All outcomes
High risk
Comment: not possible to blind participant mothers as diets were different
Blinding of outcome assessment (detection bias)
All outcomes
High risk
Comment: not possible to blind participant mothers as diets were different
Incomplete outcome data
(attrition bias)
All outcomes
Low risk
Comment: participant enrolment/study progress diagram included in paper.
Accounted for all participants
Selective reporting (reporting bias)
High risk
Comment: no specific mention or reporting of adverse effects. No response received from study author
Other bias
High risk
Comment: funded by Rice Grower's Co-operative, and intervention includes
a rice drink and rice bread daily. No further details of involvement and no response received from study author
Jakobsson 2000
Methods
Randomised, cross-over-style, baseline-control trial with 2 treatment groups
Participants
Sample size: 22 enrolled infants (7 dropped out – 3 from CH1 and 4 from CH2)
Setting: outpatient clinic of a hospital. Recruited from well-baby clinics in Malmö, Sweden
Sex: 7 boys (47%) 8 girls (53%)
Mean age: not reported (SD not reported, range 2 to 8 weeks)
Mean weight: not reported
Mean duration of colic (baseline): not reported
Mean crying (baseline): 7.36 h/d (SD 1.32)
Feeding: formula fed (100%)
Birth order: not reported
Inclusion criteria: severe colic: "crying for many times per day for at least 4 days in a week, and continuing for one week or more with each episode lasting 30 minutes to 2 hours, totaling > 3 hours per
day" (quote). Symptoms not resolved after parenting and feeding advice given to mother. Anti-spasmodic and anti-cholinergic drugs to manage the colic may have been tried prior to enrolment
Exclusion criteria: spontaneous resolution, removed for vomiting, refused to follow the protocol, families must not have previously used hydrolysed formula for their babies
Interventions
Intervention (n = 22): Alimentum hydrolysate formula with iron (Abbott Laboratories, CH1) or Nutramigen hydrolysate formula with iron (Mead Johnson Nutritionals, CH2)
Control (n = 22): baseline infant's standard formula
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Jakobsson 2000
Trusted evidence.
Informed decisions.
Better health.
Cochrane Database of Systematic Reviews
(Continued)
Duration: 1 week
Outcomes
Parents recorded daily crying time in h/d, crying intensity, and other colicky behaviour (summarised as
a percentage of the days a particular feature was observed). Formula intake and stool consistency also
recorded
Notes
Study start and end dates: not reported
COIs: not reported
Funding source: not reported
Adverse effects: none reported
Comments: none
Risk of bias
Bias
Authors' judgement
Support for judgement
Random sequence generation (selection bias)
Low risk
Quote: "at enrolment, infants were randomised to one of two feeding sequences: CH1 for a week then CH2, or CH2 for a week then CH1 in crossover
style"
Allocation concealment
(selection bias)
High risk
Comment: no details. Wrote to study author but no received response
Blinding of participants
and personnel (performance bias)
All outcomes
High risk
Comment: no details. Wrote to study author but received no response
Blinding of outcome assessment (detection bias)
All outcomes
High risk
Comment: no details. Wrote to study author but received no response
Incomplete outcome data
(attrition bias)
All outcomes
Unclear risk
Comment: some data missing after death of one of the investigators
Selective reporting (reporting bias)
Low risk
Comment: mention of clear methods and adverse effects no protocol.
Other bias
Low risk
Comment: none noted
Kanabar 2001
Methods
Double-blind, randomised, placebo-controlled cross-over trial with 2 treatment groups
Participants
Sample size: 53 infants (7 dropped out – groups not clear)
Setting: Guy & St Thomas Hospital London, UK
Sex: not reported
Mean age: not reported (SD not reported, range 3 to 13 weeks). Mothers given trial literature in the recovery room after birth and asked to get in touch if their babies had colic
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Kanabar 2001
Trusted evidence.
Informed decisions.
Better health.
Cochrane Database of Systematic Reviews
(Continued)
Mean weight: not reported
Mean duration of colic (baseline): not reported
Mean crying (baseline): not reported
Feeding: not reported
Birth order: not reported
Inclusion criteria: visit from community midwife at home to establish if baby meets trial criteria. Colic
according to Wessel criteria adapted to 14 days of symptoms, does not specify that infants were otherwise well, but recruitment was via general population and supervised by a midwife
Exclusion criteria: changes of address, and a failure to understand the dosage instructions
Interventions
Intervention (n = not stated): Colief lactase drops. For formula-fed babies, 2 drops added to every
made-up formula bottle then bottle refrigerated for 4 h before use. For breastfed babies, mother to
express 'foremilk' onto a spoon, add 4 drops of lactase, and then give this at the end of a feed (having
tested this method of short incubation with small volume of milk in vitro, using 15 mL Aptamil – not
breast milk)
Control (n = not stated): heat inactivated placebo of the lactase obtained from the manufacturer, in
identical packaging, delivered in the same way
Duration: treatment for each feed for 10 days
Outcomes
Parents noted total daily crying time in minutes over 10 days, and breath hydrogen testing done before
and after a single feed on day 10 to assess whether treatment produced 45% less crying time
Notes
Study start and end dates: not reported
COIs: Treatment products – both intervention and control – provided by Crosscare Ltd, the manufacturer of Colief, which was being tested in this study
Funding source: not reported but see COIs directly above
Adverse effects: none reported
Comments: none
Risk of bias
Bias
Authors' judgement
Support for judgement
Random sequence generation (selection bias)
Low risk
Quote: "randomly assigned by use of a predetermined computer-generated
randomisation schedule, to verum or placebo arm for 10 days"
Allocation concealment
(selection bias)
High risk
Comment: no details. Wrote to study author but received no response
Blinding of participants
and personnel (performance bias)
All outcomes
Low risk
Comment: double-blind, identical packaging of intervention and control
Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk
Comment: says double-blind but paper does not make clear whether outcome
assessors were aware of treatment arm when analysing parents' records.
Wrote to study author but received no response
Incomplete outcome data
(attrition bias)
Unclear risk
Comment: paper states that 46 (out of 53) participants were available for "cry
time analysis" (quote) and the reasons for non-availability included changes
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Kanabar 2001
All outcomes
Trusted evidence.
Informed decisions.
Better health.
Cochrane Database of Systematic Reviews
(Continued)
Selective reporting (reporting bias)
of address and failure to understand dosage instructions. A significant proportion (14/46) were found to be non-compliant with the usage of the lactase or
placebo (judged by the amount that was gone from the bottle)
Low risk
Comment: paper reports on per-protocol and intention-to-treat data but the
results from the two cross-over arms are lumped together so meta-analysis
not possible
Adverse effect data given
Other bias
High risk
Comment: this is a cross-over study but the data is lumped together so we
could not, as preferred, refer only to data from the first arm of the study. Wrote
to study author for separate data but received no response
Treatment products – both intervention and control – provided by Crosscare
Ltd, the manufacturer of Colief, which was being tested in this study
Kearney 1998
Methods
Randomised, double-blind, cross-over trial with 2 treatment groups
Participants
Sample size: 13 infants (0 dropped out)
Setting: general practices and paediatric clinics in Cork, Ireland
Sex: 9 boys (69%) 4 girls (31%)
Mean age: 53.5 days (SD 26.2, range 23 to 113 days)
Mean weight: not reported
Mean duration of colic (baseline): not reported
Mean crying (baseline): not reported
Feeding: formula fed (100%)
Birth order: not reported
Inclusion criteria: formula-fed infants with colic symptoms using a modified Wessel's criteria: full force
crying for ≥ 3 h/d for ≥ 3 d/week. Their definition did not require crying of 3 weeks or more
Exclusion criteria: 'otherwise well' (quote)
Interventions
Intervention (n = not reported): lactase (Lactaid) drops; 3 drops added to each feed, which was then
refrigerated for 24 h before feeding to the baby
Control (n = not reported): placebo supplied by manufacturer for lactase (Lactaid) drops; 3 drops
added to each feed, which was then refrigerated for 24 h before feeding to the baby
Duration: 1 week
Outcomes
Parents asked to keep a diary containing information about baby's crying time, stool habit and details
of volumes, strength and type of formula
Notes
Study start and end dates: not known
COIs: none reported
Funding source: Mediplan and Myplan, who make the lactase product Lactaid, which was used as the
intervention
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(Continued)
Adverse effects: none reported
Comments: none
Risk of bias
Bias
Authors' judgement
Support for judgement
Random sequence generation (selection bias)
Low risk
Quote: "random permutated blocks of size four to ensure that the numbers of
babies assigned to the two treatment orders were fairly even"
Allocation concealment
(selection bias)
High risk
Comment: no details. Wrote to study author but received no response
Blinding of participants
and personnel (performance bias)
All outcomes
Low risk
Quote: "preparations given in bottles marked week 1 and week 2 to ensure the
double blind nature of the trial"
Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk
Comment: no details at all. Wrote to study author but received no response
Incomplete outcome data
(attrition bias)
All outcomes
Unclear risk
Quote: "13 babies completed the trial"
Selective reporting (reporting bias)
Low risk
Comment: does not say how many began the trial
Comment: results from each cross-over arm are lumped together in the data
reports so meta-analysis not possible
Adverse effect data given
Other bias
High risk
Comment: funded by industry and no response received from study author to
confirm level of involvement
Lothe 1987
Methods
Double-blind, cross-over trial with 1 treatment group
Participants
Sample size: 65 infants (5 dropped out)
Setting: children's hospital in Malmö, Sweden
Sex: 23 boys (38%) 37 girls (62%)
Mean age: 6.38 weeks (SD 2.50, range 3 to 13)
Mean weight: not reported
Mean duration of colic (baseline): not reported
Mean crying (baseline): not reported
Feeding: predominantly or totally formula-fed infants
Birth order: not reported
Inclusion criteria: severe colic (paroxysmal abdominal pain, severe crying for several hours per day especially between 5 pm and 10 pm, abdomen distended by gas, and the wish to suck often). Infants re-
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(Continued)
ceiving dimeticonum, methylscopolaminum and dicycloverine-chloride with no effect were able to participate.
Exclusion criteria: urinary infections
Interventions
Intervention (n = not clear): one can of ProSobee (soy protein-based formula) for 1 week
Control (n = not clear): Enfamil (standard cows' milk protein-based formula) for 1 week
Duration: observation period of 1 week followed by a week of either cows' milk protein-based formula
or soy protein-based formula. The infants were then swapped onto the other formula and the results of
the 2 cross-over arms' were pooled for reporting in the paper
Outcomes
Parents given standardised protocols and asked to record the length of the crying period and any
changes in stools and vomit
Notes
Study start and end dates: 1980 (start); end date not reported
COIs: not reported
Funding source: control and intervention products manufactured and provided free by Mead Johnson
Adverse effects: not reported
Comments: formulas were provided and coded by Mead Johnson; any babies still symptomatic on soy
formula were then given cows' milk protein hydrolysate formula Nutramigen, also provided by Mead
Johnson
Risk of bias
Bias
Authors' judgement
Support for judgement
Random sequence generation (selection bias)
Unclear risk
Comment: says double-blind cross-over. Does not say randomised anywhere
Allocation concealment
(selection bias)
High risk
Comment: no details. Wrote to study author but received no response
Blinding of participants
and personnel (performance bias)
All outcomes
Low risk
Comment: says double-blind cross-over. Cans were labelled by Mead Johnson
Blinding of outcome assessment (detection bias)
All outcomes
Low risk
Quote: "at the end of the test period ... the protocols were evaluated and the
code was broken"
Incomplete outcome data
(attrition bias)
All outcomes
High risk
Comment: 60 participants (out of 65 at outset) completed the trial. No explanation of the other 5
Selective reporting (reporting bias)
High risk
Comment: reported on a per-protocol rather than an intention-to-treat basis,
no specific adverse effect data given
Other bias
Unclear risk
Comment: cans were labelled by Mead Johnson
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Lucassen 2000
Methods
Randomised, double-blind, parallel trial with 2 treatment groups
Participants
Sample size: 38 infants (5 dropouts: 2 from illness, 2 from non-compliance, and 1 referred because of
worsening symptoms – 3 intervention, 2 control)
Setting: infants recruited from community-based, well-child clinics in 6 regions of an area of Holland
with 7500 births annually, co-ordinated by the Academic Hospital of Vrije University, Amsterdam, The
Netherlands
Sex: 19 boys (50%)
Mean age: 7.7 weeks (SD not reported, range 6.4 to 8.9) intervention; 8.3 weeks (SD not reported, range
6.6 to 10.1) control
Mean weight: 4.5 kg (4.2 to 4.8) intervention; 4.9 kg (4.3 to 5.6) control
Mean duration of colic (baseline): 403 min/day (341 to 466) intervention; 328 min/day (291 to 366)
control
Mean crying (baseline): 299 min/day (251 to 347) intervention; 267 min/day (226 to 307) control
Feeding: fully formula fed or fed with mix of breast and formula, but the paper neither specifies how
many babies were also receiving breast milk, nor treated the receipt of breast milk as a confounding
factor
Birth order: not reported
Inclusion criteria: infants with good medical condition on examination by clinic doctor, thriving, formula fed (at least 1 formula feed per day), good feeding technique, < 6 months old, crying > 3 h/d on at
least 3 d/week
Exclusion criteria: history of anaphylaxis to cows' milk, previous trial of hypoallergenic feeding, refusal
to give informed consent, communication problems, referred to paediatrician, no crying problem anymore, other illness, other advice from own doctor, refusal to keep diary
Interventions
Intervention (n = 23): Nutricia whey hydrolysate formula
Control (n = 20): Nutricia standard formula
Duration: 1-week study after baseline for one week
Outcomes
Parents instructed on the use of a 24-h diary and questionnaire to assess minutes of crying per
24 h, which included the question, "Do you know which formula your infant has been using this
week?" (quote) to test for adequate blinding. Evaluation of results to include proportion of infants who,
after the intervention, would no longer meet the inclusion criteria
Notes
Study start and end dates: August 1994 (start) to October 1996 (end)
COIs: Nutricia provided the formula
Funding source: Praeventie Fonds – the Dutch National Preventative Fund
Adverse effects: none reported
Comments: none
Risk of bias
Bias
Authors' judgement
Support for judgement
Random sequence generation (selection bias)
Low risk
Comment: randomised to intervention or control group by SPSS Inc, Chicago
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(Continued)
Allocation concealment
(selection bias)
Low risk
Comment: response from study author as follows (quote), "a box containing
the formula was sent to each participating centre. Each box contained 16 cans
of formula of which 8 contained hypo-allergenic formula and 8 normal formula (of which taste and smell were changed in the direction of hypoallergenic
formula). All cans were identical and contained a sticker with a number. Each
set of two cans had the same number (so it was impossible to provide one can
with hypoallergenic formula and one can with control formula to the same infant). The local centre distributed the cans, two for each infant. The persons at
the local centre were completely unaware of the codes. The codes were generated with a random numbers list"
Blinding of participants
and personnel (performance bias)
All outcomes
Low risk
Comment: study author responded. Blinding of parents was made possible
by changing the taste and smell of the control formula in the direction of taste
and smell of the hypoallergenic formula
Blinding of outcome assessment (detection bias)
All outcomes
Low risk
Comment: study author responded. Blinding of the parents was made possible by changing the taste and smell of the control formula in the direction of
taste and smell of the hypoallergenic formula
Incomplete outcome data
(attrition bias)
All outcomes
Low risk
Comment: accounted for all participants
Selective reporting (reporting bias)
Low risk
Comment: study author contacted and we were informed that there were no
adverse effects
Other bias
Unclear risk
Comment: Nutricia provided the formula. Contact from the study author tells
us that Nutricia did not play any role except in the provision of the formulas;
they were not involved in writing or checking the manuscript
Miller 1990
Methods
Double-blind, cross-over trial with 2 treatment groups
Participants
Sample size: 15 (0 dropped out)
Setting: infants recruited from a family care centre serving the northern suburbs of Sydney, Australia
Sex: 5 boys (33%) 10 girls (67%)
Mean age: 6.5 weeks (SD 2.2, range 3 to 9)
Mean weight: not reported
Mean duration of colic (baseline): not reported
Mean crying (baseline): not reported
Feeding: breastfed (100%)
Birth order: not reported
Inclusion criteria: total duration of crying and fussing of at least 3 h in 2 consecutive 24-h periods; crying and fussing behaviour not responding to mother-craft skills, and no apparent cause for the crying
and fussing
Exclusion criteria: hydrogen concentration in breath of over 20 ppm
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(Continued)
Interventions
Intervention (n = not reported): lactase (Lactaid) in glycerol, 6 drops into baby's mouth within 5 min
of commencing feed
Control (n = not reported): glycerol with water and caramel, 6 drops into baby's mouth within 5 min of
commencing feed
Duration: 7 days in each treatment arm
Outcomes
Mothers instructed on how to complete a 24-h recording form detailing durations of infant behaviours
such as sleeping, being awake and content, crying, fussing and feeding, to determine the mean number
of minutes of crying or fussing in 24 h. Also, measurement of H2 concentrations in pre-and post-prandial breath tests, to determine the effect of yeast lactase on the mean value of each infants' breath hydrogen
Notes
Study start and end dates: July 1987 (start) to June 1988 (end)
COIs: none reported
Funding source: Sharpe Laboratories, which seemed to have produced the active and placebo preparations, but no details available as to any further extent of their involvement
Adverse effects: none reported
Comments: cross-over study but we reported on the first arm only. Based on PhD Thesis by John Miller
Risk of bias
Bias
Authors' judgement
Support for judgement
Random sequence generation (selection bias)
Unclear risk
Quote: "infants were randomly allocated"
Comment: we contacted the study author who was unable to confirm how the
random list was generated
Quote: "Dr D Shaw, Principal Consultant, Siromath, Sydney, performed the
sample size calculation and I recall that he also provided a randomisation
schema for allocation of the treatments to the breast fed, and to the formula-fed infants. I don't remember how these randomisation schema were derived"
Allocation concealment
(selection bias)
High risk
Comment: no details. Wrote to study author who was unable to confirm
whether this was done
Blinding of participants
and personnel (performance bias)
All outcomes
Low risk
Comment: described as double-blind but method not specified. Wrote to
study author who responded stating, "The active & placebo enzyme preparations were aseptically filled into plastic squeeze bottles, capped, packed into
tamper-proof plain cardboard cartons and labelled with a code by Sharpe Laboratories, Sydney. The packaged preparations were indistinguishable except
for the labelled code."
Blinding of outcome assessment (detection bias)
All outcomes
Low risk
Comment: no details. Wrote to study author who responded stating, "The active & placebo enzyme preparations were aseptically filled into plastic squeeze
bottles, capped, packed into tamper-proof plain cardboard cartons and labelled with a code by Sharpe Laboratories, Sydney. The packaged preparations were indistinguishable except for the labelled code."
Incomplete outcome data
(attrition bias)
All outcomes
Low risk
Comment: 15 entered the study, but only 12 completed the study and no reasons for non-completion are provided in the paper. We contacted the study
author who replied stating, "Of these infants, 2 ‘dropped out' – 1 on active
treatment, the other on placebo. In the former case, active treatment was discontinued after 48 hours because the parents considered the treatment wors-
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Miller 1990
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(Continued)
ened crying and fussing behaviour. In the latter case, the mother stopped using the placebo after 4 days because of lack of effect. One infant was withdrawn from the study. In this case, the mother was admitted to hospital with a
breast abscess. The infant was temporarily weaned. However, at the mother's
request, active treatment was continued."
Selective reporting (reporting bias)
Low risk
Comment: results are based on per protocol, not intention-to-treat, but all
major outcomes are reported, with adverse effect data given by study author
Other bias
Unclear risk
Comment: designed as cross-over trial but we reported on the first arm only.
Sharpe Laboratories were the study sponsor and seemed to have produced
the active and placebo preparations but no details were available as to any
further extent of their involvement. The study author confirmed no involvement.
Oggero 1994
Methods
Randomised controlled trial with 3 treatment groups
Participants
Sample size: 120 infants (0 dropped out)
Setting: Department of Pediatrics at the University of Turin, Children Hospital Regina Margherita,
Turin, Italy
Sex: not reported
Mean age: 6.2 weeks (SD not reported, range 3-12 weeks)
Mean weight: not reported
Mean duration of colic (baseline): not reported
Mean crying (baseline): not reported
Feeding: formula fed (n = 89), and breastfed (n = 31). No mention of any of the babies being mixed fed
Birth order: not reported
Inclusion criteria: infants aged 3-12 weeks suffering from severe colic, symptoms lasting for at least 2
weeks, presence of inconsolable crying, closed fists and meteorism, presence of sleep disorders, crying
for more than a total of 3 h/d, no response to common consolation procedures (pacifier, rocking, dull
continuous background noise, hot water bottle on abdomen)
Exclusion criteria: known organic causes of abdominal pain
Interventions
Intervention (n = 60): hypoallergenic dietary regimen. Breastfed babies' mothers were given a diet
containing no milk, eggs or fish; formula-fed babies were given soy milk
(If symptoms continued the symptomatic, formula-fed babies were moved onto Nutramigen for 15
days – these data are not included in our analyses)
Control (n = 60): gastrointestinal antispastic drugs. All infants given dicyclomine hydrocholoride (3
mg/kg/day divided into 3 doses per day), and no dietary modifications were made
Duration: 15 days
Outcomes
Parents asked to note the beginning and end of unexplained crying spells and to note the beginning
and end of unexplained periods of fussiness or irritability. The evaluation of treatment results based on
this information gathered by parents and written in a diary
Notes
Study start and end dates: not reported in the text. October 1991 (start) to January 1993 (end)
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(Continued)
COIs: none reported
Funding source: none reported
Adverse effects: none reported
Comments: none
Risk of bias
Bias
Authors' judgement
Support for judgement
Random sequence generation (selection bias)
Low risk
Quote: "randomly divided"
Allocation concealment
(selection bias)
High risk
Comment: participants were randomly assigned to the different groups but
the type of treatment was known (not blinded)
Blinding of participants
and personnel (performance bias)
All outcomes
High risk
Comment: not possible to blind
Blinding of outcome assessment (detection bias)
All outcomes
High risk
Comment: not a blinded study
Incomplete outcome data
(attrition bias)
All outcomes
Low risk
Comment: accounted for all participants
Selective reporting (reporting bias)
High risk
Comment: study authors reported results for all outcomes declared in the
Methods section, except adverse effects which are not reported.
Other bias
Low risk
Comment: no significant differences between groups at baseline were reported
Savino 2005
Methods
Randomised, double-blind, placebo-controlled trial with 2 treatment groups
Participants
Sample size: 93 colicky infants (5 dropped out (2 = intervention, 3 = control); 2 did not come to the second visit, 3 were excluded because of fever. Nobody withdrew because of problems related to the trial
and therefore the study population may be considered homogeneous)
Setting: recruited from patients seen at the Department of Pediatrics, Regina Margherita Children's
Hospital, University of Turin, Italy
Mean age: 4.2 weeks (SD 1.4, range not reported) intervention; 4.4 weeks (SD 1.6, range not reported)
control
Sex: 41 (46.6%) boys (18 intervention, 23 control); 47 (53.4%) girls (23 intervention, 24 control)
Mean weight: 3420 g (SD 390) intervention; 3510 g (SD 330) control
Mean duration of colic: not reported
Mean crying: 201.2 min (SD 18.3) intervention; 198.7 min (SD 16.9) control
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(Continued)
Feeding: not specified
Birth order: not specified
Inclusion criteria: colic according to Wessel criteria, breastfed, healthy infants with regular growth, 21
to 60 days old, born at term (gestational age 38 to 42 weeks), birth weight between 2500 g and 4000 g,
no clinical evidence of gastroenterological disease, and Apgar (appearance, pulse, grimace, activity,
respiration) score > 7 at 5 min after birth
Exclusion criteria: infants receiving any medication, such as antibiotics or probiotics, which could affect abdominal symptoms
Interventions
Intervention 1 (n = 41): phytotherapeutic agent (extracts of Foeniculum vulgare (fennel), Matricaria
recutita (chamomile), and Melissa officinalis (lemon balm)). Each dose of herbal agent consisted of 1
bottle, with tank cap, containing Foeniculum vulgare miller var. dulce (164.29 mg), Matricaria recutita
L. (177.69 mg), Melissa officinalis L. (96.89 mg), vitamin B1 (0.85 mg), calcium pantothenate (3.24 mg),
vitamin B6 (1.20 mg), maltodextrin (dose not specified) and syloid 244 FP (dose not specified) (ColiMil,
Milte-Milan, Italy). At the administered dosage, the herbal agent provided Foeniculum vulgare miller var.
dulce 65.71 mg/kg/d, Matricaria recutita L. 71.10 mg/kg/d, and Melissa officinalis L. 38.75 mg/kg/d
Control (n = 47): placebo looking like the phytotherapeutic agent with regard to colour, smell, taste
and package, but containing only vitamins. Each dose of placebo consisted of 1 identical bottle, with
tank cap, containing water obtained by inverted osmosis, fructose, pineapple flavour, citric acid and
sorbate potassium.
Administration: both herbal agent and placebo were administered twice a day at 5 pm and 8 pm,
some minutes before feeding, at a dosage of 2 ml/kg/d. Infants had to take treatment consecutively for
7 days
Duration: 21 days
Outcomes
Parents wrote a daily, structured diary, recording (1) the start of crying time – when the medication was
administered, (2) the end of crying time, and (3) any side effects (vomiting, sleepiness, restlessness, appetite, cutaneous reactions, constipation, diarrhoea) they observed for the 7 days of therapy and until day 21 from enrolment. Before starting treatment, parents were invited to record data on daily crying time for 3 days (days 0, 1, and 2). At days 1 and 7, infants were seen in the department, and parents
gave the diary to researchers. At day 21, after baseline, mothers were asked to complete a questionnaire about crying time during the observation period. To ensure that all parents noted crying time in a
uniform way, and to ensure that infants were given medication correctly, a researcher was always available by phone to help parents. Therapy was considered effective if crying time was reduced by ≥ 50%
per day; responders were infants who showed such a reduction in crying time
Notes
Study start and end dates: March 2001 (start) to March 2003 (end)
COIs: none reported
Funding source: funded, in part, by Milte who provided the study products but had no other role in the
study; they were not involved in writing or checking the manuscript
Adverse effects: no adverse effects
Comments: none
Risk of bias
Bias
Authors' judgement
Support for judgement
Random sequence generation (selection bias)
Low risk
Comment: this was performed by computer
Allocation concealment
(selection bias)
Low risk
Comment: conducted by a statistician not involved with the study
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(Continued)
Blinding of participants
and personnel (performance bias)
All outcomes
Low risk
Comment: placebo looked like the phytotherapeutic agent with regard to
colour, smell, taste and packaging
Quote: "Neither doctors nor parents knew whether the infants received treatment or not"
Blinding of outcome assessment (detection bias)
All outcomes
Low risk
Quote: "Neither doctors nor parents knew whether the infants received treatment or not"
Incomplete outcome data
(attrition bias)
All outcomes
Low risk
Comment: 5 infants (2 from the intervention group and 3 from the placebo
group) dropped out: 2 did not come to the second visit, and 3 were excluded
because of fever. Nobody withdrew because of problems related to the trial.
Selective reporting (reporting bias)
Low risk
Comment: study authors reported results for all outcomes declared in the
Methods section
Other bias
Low risk
Comment: no significant differences between groups at baseline were reported
Savino 2006
Methods
Prospective, randomised controlled trial with 2 treatment groups
Participants
Sample size: 267 recruited (68 withdrawn (34 intervention, 34 control); 45 (20 intervention, 25 control)
did not meet inclusion criteria by the time the study began, and 23 (14 intervention, 9 control) excluded
during the study due to missing data)
Setting: 78 general paediatricians and the Department of Pediatrics based at the University of Turin,
Children Hospital Regina Margherita, Turin, Italy
Sex: 50 (52.1%) boys intervention, 49 (47.6%) boys control; 47.9% girls intervention, 52.4% girls control
Mean age: 1.39 months (SD 0.84, range not reported) intervention; 1.29 months (SD 0.77, range not reported) control; less than 4 months at age of entry into study
Mean weight: not reported
Mean duration of colic (baseline): 5.99 colic episodes per day (SD 1.84) intervention, 5.41 colic
episodes per day (SD 1.88) control
Mean crying (baseline): not reported
Feeding: formula fed (100%)
Birth order: not reported
Inclusion criteria: infants aged less than 4 months, with infantile colic according to Wessel definition,
gestational age between 37 and 42 weeks, normal birth weight (> 2500 g), regular weight gain (more
than 150 g/week) and normal physical examination
Exclusion criteria: neonatal problems, consumption of any kind of medication during the week before
the beginning of the study and during the study period
Interventions
Intervention (n = 130): Numic oOmneo Comfort (100% whey protein, low lactose, contains GOS/FOS)
Control (n = 137): Numico Nutrilon Standard 1 formula plus simethicone (rationale being that simethicone* is as effective as placebo (Lucassen 1998), so used as placebo)
Duration: 2 weeks
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(Continued)
*Simethicone is an anti-foaming agent designed to reduce the surface tension of bubbles of gas
trapped in liquid, so they group together and can be passed more easily. As such, this is not a dietary
modification and its addition to the standard formula was intended, in this case, to assess the superiority of the intervention formula, which contained oligosaccharides thought to improve the balance of
the infant's microbiota, over the common recommendation to administer simethicone to infants with
colicky symptoms, alongside their regular milk. The oligosaccharide blend used in this study formula
was reported as being 90% galacto-oligosaccharide and 10% fructo-oligosaccharide (known as GOS/
FOS), and the formula also had a 100% whey base rather than standard formula's 60:40 whey:casein ratio, and a lower lactose level than standard formula (with additional maltodextrin and starch to thicken the milk), in addition to the cows milk proteins having been partially hydrolysed. This study was a
larger scale comparison with 103 of the infants who completed the trial randomised to the control with
standard casein-based formula plus simethicone, and 96 randomised to the intervention of a partially
hydrolysed, lower lactose, whey-based formula with starches, and supplemented with oligosaccharide
Outcomes
Questionnaire given to parents to monitor symptoms, frequency and feeding volume. On days 1, 7 and
14, infants examined by paediatricians. Feeding frequency and feeding volume was decided by the
family and not by the study protocol. The number of significant colic episodes (over 40 min in duration)
was recorded by parents daily. Study measured number of colic episodes per day (multivariate analysis
between intervention or control pairs adjusted for variables)
Notes
Study start and end dates: August 2002 (start) to January 2003 (end)
COIs: none reported
Funding source: Numico, Italy, who provided the intervention formula
Adverse effects: not reported, but we contacted the author, who is also an author on this review, who
confirmed these were recorded and none were experienced
Comments: none
Risk of bias
Bias
Authors' judgement
Support for judgement
Random sequence generation (selection bias)
Low risk
Comment: effective randomisation
Allocation concealment
(selection bias)
Low risk
Comment: sealed envelopes
Blinding of participants
and personnel (performance bias)
All outcomes
High risk
Comment: not possible because of simethicone
Blinding of outcome assessment (detection bias)
All outcomes
Low risk
Comment: blinding of outcome assessment performed by statistician
Incomplete outcome data
(attrition bias)
All outcomes
Low risk
Comment: 68/267 excluded at the end of the trial for non-adherence to intervention or control, or because lost to follow-up – see above under 'Participants'. Clarified by study author
Selective reporting (reporting bias)
Low risk
Comment: accounted for all participants. Study authors confirmed no adverse
effects experienced
Other bias
Unclear risk
Comment: study supported by funds from Numico, Italy. They were not involved in writing or checking the manuscript.
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Taubman 1988
Methods
Randomised controlled trial with 2 treatment groups. For our purposes, we have labelled 'maternal
dairy-free diet' and 'parental counselling plus usual diet', as 'intervention' and 'control' respectively.
Participants
Sample size: 11 (1 dropout) in group 1; 10 (0 dropouts) in group 2
Setting: private practice and the gastroenterology clinic at the Children's Hospital of Philadelphia,
Pennsylvania, USA
Sex: not reported
Mean age: 5.4 weeks (SD 2.2, range not reported) intervention; 6.5 weeks (SD 1.8, range not reported)
control
Mean weight: not reported
Mean duration of colic (baseline): 3.75 weeks (SD 5.8) intervention; 4.85 weeks (SD 4.12) control
Mean crying (baseline): 3.21 h/d (SD 1.10) intervention; 3.19 h/d (SD 0.69) control
Feeding: not reported
Birth order: 3 first born in each group (30%)
Inclusion criteria: infants crying for more than 2 h/d, younger than 3 months of age, normal growth
and development, normal physical findings, no history of diarrhoea or vomiting, and receiving enough
milk
Exclusion criteria: babies already receiving Nutramigen hydrolysed milk or breastfed babies whose
mothers are already eating dairy-free
Interventions
Intervention* (n = 11): maternal dairy-free diet if baby breastfed, or Nutramigen hydrolysed casein
formula if baby formula fed
Control (n = 10): parental counselling plus usual diet
Duration: 9 days duration in each treatment arm of study
*The intervention group went on to have counselling along with return to usual diet. This is not included in our analysis as is the second treatment arm, and we only used data from first treatment arm.
Outcomes
Parents kept a diary of the infants behaviour, in the prescribed manner, during both phases of the
study and returned them to the investigator every 2 or 3 days
Notes
Study start and end dates: not reported
COIs: none reported, but see funding source directly below
Funding source: funded, in part, by Mead Johnson, who provided the intervention formula
Adverse effects: not recorded
Comments: this was a 2-phased, randomised study with 11 infants in the counselling group (group 1)
and 10 in the 'dairy and soy free' group (group 2), although the first group lost 1 participant from the
study in the first few days and did not include that infant's data in the results. 3 infants in the counselling group were breastfed and 4 infants in the dairy and soy free group were breastfed. This study
was designed to show the effectiveness of counselling by using dietary changes as a comparison.
Risk of bias
Bias
Authors' judgement
Support for judgement
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Taubman 1988
Trusted evidence.
Informed decisions.
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(Continued)
Random sequence generation (selection bias)
Low risk
Comment: effective randomisation. Investigator had no knowledge of the allocation until after consent was given
Allocation concealment
(selection bias)
High risk
Comment: no details
Blinding of participants
and personnel (performance bias)
All outcomes
High risk
Comment: not possible given the nature of the trial
Blinding of outcome assessment (detection bias)
All outcomes
High risk
Comment: no details. Wrote to study author but received no response
Incomplete outcome data
(attrition bias)
All outcomes
Unclear risk
Comment: accounted for all participants, though paper reports per protocol,
not intention-to-treat, results after one participant dropped out of the control
group
Selective reporting (reporting bias)
High risk
Comment: paper reports per protocol, not intention-to-treat, results after one
participant dropped out of the control group. Adverse effects not reported
Other bias
High risk
Comment: funded, in part, by Mead Johnson, who provided the intervention
formula
Treem 1991
Methods
Double-blind, randomised, 2-period, cross-over trial with 2 treatment groups
Participants
Sample size: 33 infants (6 dropped out – sequence group not clear)
Setting: paediatricians in the greater Hartford community, Connecticut, USA
Sex: 13 boys (48%) 14 girls (52%)
Mean age: 34 days (SD not reported, range 10 to 54)
Mean weight: not reported
Mean duration of colic (baseline): not reported
Mean crying (baseline): not reported
Feeding: formula fed (100%)
Birth order: 15 first born
Inclusion criteria: crying as if in pain, crying suddenly, crying continuously for more than 15 min at a
time, and difficult or impossible to console during these crying spells, with colic defined as more than 3
h crying or fussing per day on at least 3 days out of 6 successive days, birth weight > 2500 g, normal gestational age, absence of neonatal problems, normal weight gain (> 150 g/week), normal physical examination
Exclusion criteria: infants on medications during the first week before or during the study
Interventions
Intervention (n = 12): Isomil with soy polysaccharide added to increase dietary fibre (mean values 14.1
g dietary fibre per litre)
Control (n = 15): Isomil with nothing added (mean values 3.1 g dietary fibre per litre)
Dietary modifications for infantile colic (Review)
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Trusted evidence.
Informed decisions.
Better health.
Cochrane Database of Systematic Reviews
(Continued)
Duration: baseline for 1 week before beginning study. Cross-over study, including 3-day washout between 2 × 9-day-long arms of study. Patients seen 5 times during the study: at the beginning of the
baseline period, at each of the 2 × 9-day study periods, at the end of the last 9-day period, and at the
30- to 35-day follow-up period. Parents also contacted by telephone at least once during each of the 2 ×
9-day study periods
Outcomes
Daily behaviour, feeding, and stool diaries completed for 27 days. At the end of this time, parents asked
to indicate during which study period the symptoms of colic were most alleviated and whether the infant's symptoms were alleviated during one of the study periods more than during any time before the
study. We did not include these data in our analysis as we were looking only at the first arm.
Results for crying and fussing in min per 24 h, but aggregated cross-over data
Notes
Study start and end dates not reported
COIs: none reported
Funding source: supported by grants from Ross Laboratories
Adverse effects: not reported
Comments: none
Risk of bias
Bias
Authors' judgement
Support for judgement
Random sequence generation (selection bias)
Low risk
Comment: randomised
Allocation concealment
(selection bias)
High risk
Comment: no details. Wrote to study author but received no response
Blinding of participants
and personnel (performance bias)
All outcomes
Low risk
Comment: double-blind and disguised
Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk
Comment: no details. Wrote to study author but received no response
Incomplete outcome data
(attrition bias)
All outcomes
Low risk
Comment: accounted for all participants
Selective reporting (reporting bias)
High risk
Comment: accounted for all participants, adverse effects not reported
Other bias
High risk
Comment: supported by grants from Ross Laboratories who make Isomil. No
further details of involvement were available from the study author
COIs: conflicts of interest; GP: general practitioner; HV: health visitor; SD: standard deviation; SPSS: Statistical Package for the Social
Sciences.
Characteristics of excluded studies [ordered by study ID]
Dietary modifications for infantile colic (Review)
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Study
Reason for exclusion
Arikan 2008
Appears to be randomised, but study authors state that in order to prevent discontinuation of
breastfeeding, only participants who were formula fed went into the group receiving hydrolysed
formula, so, in fact, not random
Barr 1991
Not suffering with colic on entry to study
Bellaiche 2018
Not an RCT
Berseth 2009
No definition of colic: "parent-identified as very fussy or extremely fussy in the baseline tolerance
evaluation" (quote)
Buchanan 1998
Letter to Editor of BMJ
Campeotto 2011
Not suffering with colic on entry to study
Dupont 2010
Using probiotics to treat so not dietary modification
Evans 1981
Not an RCT – no control
Gerrard 1984
Narative review only
Giovannini 2014
Not suffering with colic on entry to study
Iacono 1991
Not an RCT – no control
Iacovou 2018
Recruited infants did not match infantile colic criteria reported in their own Methods
Imanieh 2004
Study looking for skin prick test as predictor of cows' milk protein allergy in colicky infants
Infante 2011
Not colic by our definition: only 35% (7 out of 20) infants included in analysis cried for more than 3
h/d at baseline
Jakobsson 1983
Not an RCT or quasi-RCT
Koonce 2011
Narrative review only
Laws 1991
Letter to Editor of Journal of Pediatrics
Liebman 1981
Not an RCT or quasi-RCT
Nocerino 2012
Conference abstract; not randomised
Pärtty 2015
Using probiotics to treat so not dietary modification
Rozé 2012
Not suffering with colic on entry to study
Sargsyan 2006
Letter to Editor of European Journal of Pediatrics
Savilahti 1989
Not an RCT or quasi-RCT
Savino 2003
Not colic by our definition
Sherman 2015
Not suffering with colic on entry to study
Vandenplas 2017
Not suffering with colic on entry to study
Dietary modifications for infantile colic (Review)
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Trusted evidence.
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Study
Reason for exclusion
Vivatvakin 2010
Not suffering with colic on entry to study
Xinias 2017
Not an RCT – consecutive entry
Cochrane Database of Systematic Reviews
RCT: randomised controlled trial.
Characteristics of ongoing studies [ordered by study ID]
NCT01721850
Trial name or title
Title: Evaluation of safety and efficacy of new infant formula in infantile colic (Coco)
Official title: Evaluation of the safety and efficacy of new infant formula and its effects on the gastrointestinal tolerance (crying time) in infantile colic: a double-blind, randomised, controlled intervention study
Methods
Double-blind, randomised-controlled intervention study
Participants
Inclusion criteria
1.
2.
3.
4.
5.
6.
7.
8.
Healthy, term infants
Participants appropriate for gestational age, between 35 and 41 weeks
Participants between 15 and 60 days old
Participants with birth weight between 2500 g and 4200 g, and with regular weight gain (≥ 150 g/
week)
Diagnosis of infantile colic according to modified Wessel criteria (crying episodes lasting ≥ 3 h/d
and occurring ≥ 3 d/week for at least 1 week)
Participants exclusively formula-fed at study entrance
Day care of the child only by mother or father or both
Provide written informed consent in accordance with legal requirement
Exclusion criteria
1. Neonatal problems (respiratory distress, asphyxia, Hypoglycaemia, sepsis, necrotising entercolitis)
2. Clinical evidence of chronic illness or gastrointestinal disorders (gastroesophageal reflux, gastroenteritis)
3. Assumption of any kind of medication (except vitamin D, vitamin K and fluoride prophylaxis) during the week before the beginning of the study and during the study period
4. Participants receiving formula for special medical purposes
5. Exclusively breastfed infants
6. Feeding of supplemental probiotics or prebiotics (or both) 2 weeks prior to inclusion
7. Allergic diseases (manifest atopic dermatitis, cows' milk allergy)
8. Participation in any other clinical intervention
Interventions
Parallel assignment with 3 arms:
1. control formula (standard formula)
2. intervention formula 1 (infant formula with hydrolysed protein (type I) and pre- and probiotics
3. intervention formula 2 (infant formula with hydrolysed protein (type II) and pre- and probiotics
Outcomes
Primary outcome
1. Daily total crying time (time frame: 28 days); evaluation of the difference in the average reduction
of daily crying time after 28 days of intervention between the intervention and control groups
Dietary modifications for infantile colic (Review)
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NCT01721850
Trusted evidence.
Informed decisions.
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(Continued)
Secondary outcomes
1. Growth parameters (time frame: 90 days); determination of body weight, length, head circumference
2. Tolerance evaluated by stool characteristics, gastrointestinal disorders and side effects (time
frame: 28 days); stool characteristics: frequency, consistency and colour; gastrointestinal disorders: regurgitation, obstipation; side effects: vomiting, diarrhoea, skin reactions
3. Formula intake (time frame: 28 days); evaluation of average daily drinking amount and formula
acceptance
4. Intestinal microbiota (time frame: 0 to 28 days); evaluation of changes in the composition of the
intestinal microbiota (lactobacilli, bifidobacteria, coliforms) after intervention
Starting date
December 2011
Contact information
Name: Christina Hecht
Email: Christina.hecht@hipp.de
Telephone: 00498441757855
Notes
Status: recruiting
Funding source: HiPP GmbH & Co. Vertrieb KG
NCT02813772
Trial name or title
Title: Efficacy of a partially hydrolyzed formula, containing Lactobacillus reuteri, for infant colic
Official title: Efficacy of a partially hydrolyzed formula, containingLactobacillus reuteri, for infant
colic: a double blind, randomised-controlled trial
Methods
Double-blind, randomised controlled trial
Participants
Inclusion criteria
1.
2.
3.
4.
5.
6.
Full-term infants (≥ 37 weeks gestation at birth)
Exclusively formula-fed infants at time of enrolment
Infants suffering from infantile colic according to Rome III criteria
Age < 4 months of life
5-min Apgar (appearance, pulse, grimace, activity, respiration) score ≥ 7
Birth weight ≥ 2500 g
Exclusion criteria
1. Consumption of formula containing probiotics, partially hydrolysed formula or with reduced lactose content at time of enrolment
2. Major medical problem or acute illness, including gastroesophageal reflux, cows' milk protein allergy
3. History of antibiotic treatment before or during the study
4. History of probiotic or L reuteri supplementation
5. History of any allergies to any of the ingredients in the probiotic L reuteri
6. Concurrent participation in another clinical trial
7. Birth weight < 2500 g
8. Failed to thrive
9. Breastfed infants
Dietary modifications for infantile colic (Review)
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NCT02813772
Trusted evidence.
Informed decisions.
Better health.
Cochrane Database of Systematic Reviews
(Continued)
10.NAN infant formula (to avoid the formula switch effect)
Interventions
Parallel assignment: a partially hydrolysed formula with reduced lactose content and L reuteri versus a standard formula
Outcomes
Primary outcome
1. Whether the administration of a partially hydrolysed formula with reduced lactose content and
L reuteri is beneficial in infantile colic in reducing the infant crying duration (time frame: 7, 14,
21, 28 days, 2 and 3 months); infant crying duration (min/d) at 7, 14, 21, 28 days, 2 and 3 months
postintervention
Secondary outcomes
1. Whether the administration of a partially hydrolysed formula with reduced lactose content and L
reuteri is beneficial in infantile colic in reducing the infant crying duration (time frame: 28 days);
percentage of responders at 28 days postintervention. A response to the treatment will be defined
as 50% of reduction of infant crying.
2. Whether the administration of a partially hydrolysed formula with reduced lactose content and L
reuteri is beneficial in infantile colic in increasing infant sleep (time frame: 7, 14, 21, 28 days, 2 and
3 months); longer infant sleep duration at 7, 14, 21, 28 days, 2 and 3 months postintervention
3. The effect of a partially hydrolysed formula on quality of life of the enrolled patients (time frame:
3 months); reduction of mean scores of a standardised measure for children's quality of life
4. The effect of a partially hydrolysed formula on quality of life of parents (time frame: 3 months);
reduction of mean scores of a standardised measure for parents' quality of life
5. The effect of this infant formula enriched with L reuteri on faecal microbiome of colicky infants
(time frame: 2 months); changes in gut microbiome
6. Changes in stool frequency and consistency (time frame: 28 days); changes in stool frequency and
consistency
7. Parental perception of colic severity (visual analog scale, 0 to 10) (time frame: 28 days); parental
perception of colic severity (visual analog scale, 0 to 10)
8. Parental perception of sleep quality (visual analog scale, 0 to 10) (time frame: 28 days); parental
perception of sleep quality (visual analog scale, 0 to 10)
Starting date
November 2015
Contact information
Name: Annamaria Staiano
Email: staiano@unina.it
Telephone: none provided
Notes
Status: recruiting
Funding source: Federico II University
NCT03329222
Trial name or title
Title: An infant formula trial on dietary management of infantile colic
Official title: A randomised, double-blind, controlled, multi-centre study to assess the efficacy of
an infant formula in the dietary management of infantile colic
Methods
Double-blind, randomised controlled trial
Participants
Inclusion criteria
1. Infants aged 21-56 days (both inclusive)
Dietary modifications for infantile colic (Review)
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NCT03329222
Trusted evidence.
Informed decisions.
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(Continued)
2.
3.
4.
5.
6.
7.
Gestation age 37-42 weeks
Normal birth weight for gestational age and gender
5-min Apgar (appearance, pulse, grimace, activity, respiration) score >7
Diagnosed with infantile colic
Fully formula fed for at least 7 days before randomisation
Written informed consent from the parent or legal representative (or both)
Exclusion criteria
1. Any plausible cause of inconsolable crying as judged by the investigator
2. Presence of non-functional vomiting or failure to thrive
3. Presence of any congenital defects in the gastrointestinal system or other defects preventing oral
nutrition
4. Combination of congenital condition or previous or current illness/infection and (or) medication
use that could interfere with the main study outcomes
5. Known cows' milk protein allergy, lactose intolerance or galactosaemia, including presence of
any allergic manifestations
6. Received any special formula (e.g. lactose free, hydrolysed protein)
7. Received any of the following products/medication within 7 days before randomisation: probiotics, systemic antibiotics, prokinetics, proton pump inhibitors
8. Twins or triplets or other infant(s) < 6 months of age living in the same household
9. Incapability of the parent(s) to comply with the study protocol or investigator's uncertainty about
the willingness or ability of the participant to comply with protocol requirements
10.Current participation in another clinical study involving investigational or marketed products
Interventions
An infant formula that contains specific hydrolysed proteins with a fat-blend, prebiotic mixture,
starch and reduced lactose versus standard cows' milk with prebiotic mixture
Outcomes
Primary outcome
1. Daily inconsolable crying time using data recorded on participant's diaries (time frame: 6 weeks);
daily inconsolable crying time over 6 weeks
Secondary outcome
1. Daily crying time using data recorded on participant's diaries (time frame: 6 weeks); daily crying
time over 6 weeks of intervention
2. Daily fussing time using data recorded on participant's diaries (time frame: 6 weeks); daily fussing
time over 6 weeks of intervention
3. Daily inconsolable fussing time using data recorded on participant's diaries (time frame: 6 weeks);
daily inconsolable fussing time over 6 weeks of intervention
4. Daily stool frequency using data recorded on participant's diaries (time frame: 6 weeks); daily
stool frequency over 6 weeks of intervention
5. Daily stool consistency using data recorded on participant's diaries (time frame = 6 weeks); daily
stool consistency over 6 weeks of intervention
6. The frequency of participants' gastrointestinal symptoms of digestion in the 7-day period prior
to the visit using the Infant Gastrointestinal Symptoms questionnaire (time frame: 6 weeks); gastrointestinal symptoms using the Infant Gastrointestinal Symptoms Questionnaire during the 6week intervention period
7. The intensity of participants' gastrointestinal symptoms of digestion in the 7-day period prior to
the visit using the Infant Gastrointestinal Symptoms Questionnaire (time frame: 6 weeks); gastrointestinal symptoms using the Infant Gastrointestinal Symptoms Questionnaire during the 6week intervention period
Starting date
27 October 2017
Contact information
Name: Wan Wen Tee; Anneke Ravensbergen
Dietary modifications for infantile colic (Review)
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NCT03329222
Trusted evidence.
Informed decisions.
Better health.
Cochrane Database of Systematic Reviews
(Continued)
Email: wanwen.tee@danone.com; anneke.ravensbergen@danone.com
Telephone: +65 68309466; +65 6830 9419
Notes
Status: recruiting
Funding source: Danone Asia Pacific Holdings Pte, Ltd
APPENDICES
Appendix 1. Search strategies
Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library
#1[mh Colic]
#2colic*
#3((stomach or abdominal or abdomen*) near/3 (spasm* or pain* or cramp*))
#4((gastric or gastro*) near/3 (spasm* or pain* or cramp*))
#5[mh Crying]
#6(cry or crying or cries)
#7{or #1-#6}
#8[mh Infant]
#9(baby or babies or child* or infant* or newborn* or neonate*)
#10{or #8-#9}
#11[mh Milk]
#12[mh "Milk, Human"]
#13[mh "Breast Feeding"]
#14(breastfeed* or "breast feed*" or breastfed or "breast fed" or breastmilk* or "breast milk*" or milk*)
#15[mh ^Hypersensitivity]
#16[mh "Food Hypersensitivity"]
#17[mh ^Allergens]
#18[mh "Lactose Intolerance"]
#19(allerg* or hypoallerg* or hypo next allerg* or hyperallerg* or hyper next allerg* or hypersensitiv* or hyper next sensitiv* or intoleran*
or non next allerg* or nonallerg* or sensitiv*)
#20[mh "Infant Food"]
#21(formula* or bottle next fed* or bottlefed* or bottlefeed* or bottle next feed*)
#22[mh Hydrolysis]
#23(hydrolys* or hydrolyz*)
#24[mh Prebiotics]
#25[mh ^"Amino acids"] 1
#26(amino next acid* or aminoacid* or casein* or fibre* or fiber* or prebiotic* or pre next biotic* or soy* or whey*)
#27[mh "Dietary Proteins"]
#28[mh "diet therapy"/FS]
#29diet*
#30[mh "Dairy Products"]
#31[mh Fishes]
#32[mh Eggs]
#33[mh Gluten]
#34[mh Nuts]
#35(cheese* or dairy or egg* or fish* or gluten* or wheat* or nut* or peanut* or lactose* or yogurt* or yoghurt*)
#36{or #11-#35}
#37#7 and #10 and #36 in Trials
MEDLINE Ovid
1 Colic/
2 colic$.tw.
3 ((stomach or abdominal or abdomen$) adj3 (spasm$ or pain$ or cramp$)).tw.
4 ((gastric or gastro$) adj3 (spasm$ or pain$ or cramp$)).tw.
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5 crying/
6 (cry or crying or cries).tw.
7 or/1-6
8 exp Infant/
9 (baby or babies or child$ or infant$ or newborn$ or neonate$).tw.
10 8 or 9
11 7 and 10
12 Milk/
13 Milk, Human/
14 Breast Feeding/
15 (breastfe?d$ or breast fe?d$ or breastmilk$ or breast-milk$ or milk$).tw.
16 Hypersensitivity/
17 exp Food Hypersensitivity/
18 Allergens/
19 Lactose Intolerance/
20 (allerg$ or hypoallerg$ or hypo-allerg$ or hyperallerg$ or hyper-allerg$ or hypersensitiv$ or hyper-sensitiv$ or intoleran$ or non-allerg
$ or nonallerg$ or sensitiv$).tw.
21 exp Infant Food/
22 (formula$ or bottle fed$ or bottlefed$ or bottlefeed$ or bottle feed$).tw.
23 Hydrolysis/
24 (hydrolys$ or hydrolyz$).tw.
25 Prebiotics/
26 Amino acids/)
27 (amino acid$ or aminoacid$ or casein$ or fibre$ or fiber$ or prebiotic$ or pre-biotic$ or soy$ or whey$).tw.
28 exp Dietary Proteins/
29 diet therapy.fs.
30 diet$.tw.
31 exp Dairy Products/
32 exp Eggs/
33 Fishes/
34 Gluten/
35 Nuts/
36 (cheese$ or dairy or egg$ or fish$ or gluten$ or wheat$ or nut$ or peanut$ or lactose$ or yog?urt$).tw.
37 or/12-36
38 11 and 37
39 randomized controlled trial.pt.
40 controlled clinical trial.pt.
41 randomi#ed.ab.
42 placebo$.ab.
43 drug therapy.fs.
44 randomly.ab.
45 trial.ab.
46 groups.ab.
47 or/39-46
48 exp Animals/ not Humans.sh.
49 47 not 48
50 38 and 49
MEDLINE In-Process & Other Non-Indexed Citations Ovid
1 colic$.mp.
2 ((stomach or abdominal or abdomen$) adj3 (spasm$ or pain$ or cramp$)).mp.
3 ((gastric or gastro$) adj3 (spasm$ or pain$ or cramp$)).mp.
4 (cry or crying or cries).mp.
5 or/1-4
6 (baby or babies or child$ or infant$ or newborn$ or neonat$).mp.
7 5 and 6
8 (breastfe?d$ or breast fe?d$ or breastmilk$ or breast-milk$ or milk$).mp.
9 (allerg$ or hypoallerg$ or hypo-allerg$ or hyperallerg$ or hyper-allerg$ or hypersensitiv$ or hyper-sensitiv$ or intoleran$ or non-allerg
$ or nonallerg$ or sensitiv$).mp.
10 (formula$ or bottle fed$ or bottlefed$ or bottlefeed$ or bottle feed$).mp.
11 (hydrolys$ or hydrolyz$).mp.
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12 (amino acid$ or aminoacid$ or casein$ or fibre$ or fiber$ or prebiotic$ or pre biotic$ or soy$ or whey$).mp.
13 diet$.mp.
14 (cheese$ or dairy or egg$ or fish$ or gluten$ or wheat$ or nut$ or peanut$ or lactose$ or yog?urt$).mp.
15 or/8-14
16 7 and 15
MEDLINE EPub Ahead of Print Ovid
1 colic$.mp.
2 ((stomach or abdominal or abdomen$) adj3 (spasm$ or pain$ or cramp$)).mp.
3 ((gastric or gastro$) adj3 (spasm$ or pain$ or cramp$)).mp.
4 (cry or crying or cries).mp.
5 or/1-4
6 (baby or babies or child$ or infant$ or newborn$ or neonat$).mp.
7 5 and 6
8 (breastfe?d$ or breast fe?d$ or breastmilk$ or breast-milk$ or milk$).mp.
9 (allerg$ or hypoallerg$ or hypo-allerg$ or hyperallerg$ or hyper-allerg$ or hypersensitiv$ or hyper-sensitiv$ or intoleran$ or non-allerg
$ or nonallerg$ or sensitiv$).mp.
10 (formula$ or bottle fed$ or bottlefed$ or bottlefeed$ or bottle feed$).mp.
11 (hydrolys$ or hydrolyz$).mp.
12 (amino acid$ or aminoacid$ or casein$ or fibre$ or fiber$ or prebiotic$ or pre biotic$ or soy$ or whey$).mp.
13 diet$.mp.
14 (cheese$ or dairy or egg$ or fish$ or gluten$ or wheat$ or nut$ or peanut$ or lactose$ or yog?urt$).mp.
15 or/8-14
16 7 and 15
Embase Ovid
1 colic/
2 colic$.tw.
3 ((gastric or gastro$) adj3 (spasm$ or pain$ or cramp$)).tw.
4 crying/
5 (cry or crying or cries).tw.
6 or/1-5
7 exp infant/
8 (baby or babies or child$ or infant$ or newborn$ or neonate$).tw.
9 7 or 8
10 6 and 9
11 infantile colic/
12 10 or 11
13 milk/
14 breast milk/
15 breast feeding/
16 (breastfe?d$ or breast fe?d$ or breastmilk$ or breast-milk$ or milk$).tw.
17 hypersensitivity/
18 exp nutritional intolerance/
19 exp allergen/
20 lactose intolerance/
21 (allerg$ or hypoallerg$ or hypo-allerg$ or hyperallerg$ or hyper-allerg$ or hypersensitiv$ or hyper-sensitiv$ or intoleran$ or non-allerg
$ or nonallerg$ or sensitiv$).tw.
22 exp baby food/
23 (formula$ or bottle fed$ or bottlefed$ or bottlefeed$ or bottle feed$).tw.
24 hydrolysis/
25 prebiotic agent/
26 amino acid/
27 (amino acid$ or aminoacid$ or casein$ or fibre$ or fiber$ or prebiotic$ or pre-biotic$ or soy$ or whey$).tw.
28 exp dairy product/
29 protein intake/
30 diet$.tw.
31 egg/
32 fish/
33 exp nut/
34 gluten/
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35 gluten free diet/
36 (cheese$ or dairy or egg$ or fish$ or gluten$ or wheat$ or nut$ or peanut$ or lactose$ or yog?urt$).tw.
37 or/13-36
38 12 and 37
39 Randomized controlled trial/
40 controlled clinical trial/
41 Single blind procedure/
42 Double blind procedure/
43 triple blind procedure/
44 Crossover procedure/
45 (crossover or cross-over).tw.
46 ((singl$ or doubl$ or tripl$ or trebl$) adj1 (blind$ or mask$)).tw.
47 Placebo/
48 placebo.tw.
49 prospective.tw.
50 factorial$.tw.
51 random$.tw.
52 assign$.ab.
53 allocat$.tw.
54 volunteer$.ab.
55 or/39-54
56 38 and 55
CINAHL Plus EBSCOhost (Cumulative Index to Nursing and Allied Health Literature)
S36 S13 AND S35
S35 S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR
S31 OR S32 OR S33 OR S34
S34 (cheese* or dairy or egg* or fish* or gluten* or wheat* or nut* or peanut* or lactose* or yog#urt*)
S33 (MH "Nuts+")
S32 (MH "Gluten") OR (MH "Diet, Gluten-Free")
S31 (MH "Fish")
S30 (MH "Eggs")
S29 (MH "Dairy Products+")
S28 diet*
S27 (MH "Dietary Proteins+")
S26 ("amino acid*" or aminoacid* or casein* or fibre* or fiber* or prebiotic* or "pre-biotic*" or soy* or whey*)
S25 (MH "Amino Acids")
S24 (MH "Prebiotics")
S23 (hydrolys* or hydrolyz*)
S22 (formula* or bottle-fe#d* or bottlefe#d*
S21 (MH "Infant Food+")
S20 (allerg* or hypoallerg* or hypo-allerg* or hyperallerg* or hyper-allerg* or hypersensitiv* or hyper-sensitiv* or intoleran* or non-allerg*
or nonallerg* or sensitiv *)
S19 (MH "Allergens")
S18 (MH "Food Hypersensitivity")
S17 (MH "Milk Hypersensitivity")
S16 (breastfe#d* OR breast-fe#d* or breastmilk or breast-milk or milk)
S15 (MH "Breast Feeding")
S14 (MH "Milk, Human")
S13 S11 OR S12
S12 (MH "Infant Colic")
S11 S7 AND S10
S10 S8 OR S9
S9 (MH "Infant+")
S8 TI(baby or babies or child* or infant* or newborn* or neonate*) OR AB(baby or babies or child* or infant* or newborn* or neonate*)
S7 S1 OR S2 OR S3 OR S4 OR S5 OR S6
S6 (cry or crying or cries)
S5 (MH "Crying")
S4 ((gastric or gastro*) N3 (spasm* or pain* or cramp*))
S3 ((stomach or abdominal or abdomen*) N3 (spasm* or pain* or cramp*))
S2 colic*
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S1 (MH "Colic")
PsycINFO Ovid
1 crying/
2 colic$.tw.
3 (cry or crying or cries).tw.
4 ((gastric or gastro$) adj3 (spasm$ or pain$ or cramp$)).tw.
5 ((stomach or abdominal or abdomen$) adj3 (spasm$ or pain$ or cramp$)).tw.
6 or/1-5
7 (baby or babies or child$ or infant$ or newborn$ or neonate$).tw.
8 (infancy 2 23 mo or neonatal birth 1 mo).ag.
9 7 or 8
10 breast feeding/
11 (breastfe?d$ or breast fe?d$ or breastmilk$ or breast-milk$ or milk$).tw.
12 bottle feeding/
13 Food Allergies/
14 antigens/
15 (allerg$ or hypoallerg$ or hypo-allerg$ or hyperallerg$ or hyper-allerg$ or hypersensitiv$ or hyper-sensitiv$ or intoleran$ or non-allerg
$ or nonallerg$ or sensitiv$).tw.
16 (formula$ or bottle fed$ or bottlefed$ or bottlefeed$ or bottle feed$).tw.
17 (hydrolys$ or hydrolyz$).tw.
18 dietary supplements/
19 (amino acid$ or aminoacid$ or casein$ or fibre$ or fiber$ or prebiotic$ or pre-biotic$ or soy$ or whey$).tw.
20 Amino acids/
21 diet$.tw.
22 (cheese$ or dairy or egg$ or fish$ or gluten$ or wheat$ or nut$ or peanut$ or lactose$ or yog?urt$).tw.
23 or/10-22
24 6 and 9 and 23
25 clinical trials/
26 random$.tw.
27 (allocat$ or assign$).tw.
28 ((clinic$ or control$) adj trial$).tw.
29 ((control$ or experiment$ or intervention$) adj3 group$).tw.
30 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
31 (crossover$ or "cross over$").tw.
32 random sampling/
33 Experiment Controls/
34 Placebo/
35 placebo$.tw.
36 exp program evaluation/
37 treatment effectiveness evaluation/
38 ((effectiveness or evaluat$) adj3 (stud$ or research$)).tw.
39 or/25-38
40 24 and 39
Science Citation Index (SCI) and Social Sciences Citation Index (SSCI); Web of Science
# 12 #11 AND #10
# 11 TS=(random* or control* or trial* or placebo* or group* or blind* or double-blind*) .
# 10 #9 AND #1
# 9 #8 OR #7 OR #6 OR #5 OR #4 OR #3 OR #2
# 8 TS= (cheese* or dairy or egg* or fish* or gluten* or wheat* or nut* or peanut* or lactose* or yog*urt*)
# 7 TS=(hydrolys* or hydrolyz*)
# 6 TS=("amino acid*" or aminoacid* or casein* or fibre* or fiber* or prebiotic* or pre-biotic* or soy* or whey*)
# 5 TS= (allerg* or hypoallerg* or hypo-allerg* or hyperallerg* or hyper-allerg* or hypersensitiv* or hyper-sensitiv* or intoleran* or nonallerg* or nonallerg* or sensitiv *)
# 4 TS=(formula* or bottle-fed or bottle-feed* or bottlefeed* or bottlefed)
# 3 TS=(breastfed or breast-fed or breastfeed* or breast-feed* )
# 2 TS=(diet*)
#1 TS=((colic* or crying or cries or cry) Near/10 (infant* or baby or babies or child*))
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Conference Proceedings Citation Index - Science (CPCI-S) and Conference Proceedings Citation Index - Social Science &
Humanities (CPCI-SS&H); Web of Science
#10 #9 AND #1
#9 #8 OR #7 OR #6 OR #5 OR #4 OR #3 OR #2
#8 TS= (cheese* or dairy or egg* or fish* or gluten* or wheat* or nut* or peanut* or lactose* or yog*urt*)
#7 TS=(hydrolys* or hydrolyz*)
#6 TS=("amino acid*" or aminoacid* or casein* or fibre* or fiber* or prebiotic* or pre-biotic* or soy* or whey*)
#5 TS= (allerg* or hypoallerg* or hypo-allerg* or hyperallerg* or hyper-allerg* or hypersensitiv* or hyper-sensitiv* or intoleran* or nonallerg* or nonallerg* or sensitiv *)
#4 TS=(formula* or bottle-fed or bottle-feed* or bottlefeed* or bottlefed)
#3 TS=(breastfed or breast-fed or breastfeed* or breast-feed* )
#2 TS=(diet*)
#1 TS=((colic* or crying or cries or cry) Near/10 (infant* or baby or babies or child*))
Cochrane Database of Systematic Reviews (CDSR), part of the Cochrane Library
#1[mh Colic]
#2colic*:ti,ab
#3[mh Crying]
#4(cry or crying or cries):ti,ab
#5{or #1-#4}
#6[mh Infant]
#7(baby or babies or child* or infant* or newborn* or neonate*):ti,ab
#8{or #6-#7}
#9#5 and #8
#10[mh Milk]
#11[mh "Milk, Human"]
#12[mh "Breast Feeding"]
#13(breastfeed* or "breast feed*" or breastfed or "breast fed" or breastmilk* or "breast milk*" or milk*):ti,ab
#14[mh ^Hypersensitivity]
#15[mh "Food Hypersensitivity"]
#16[mh ^Allergens]
#17[mh "Lactose Intolerance"]
#18(allerg* or hypoallerg* or hypo next allerg* or hyperallerg* or hyper next allerg* or hypersensitiv* or hyper next sensitiv* or intoleran*
or non next allerg* or nonallerg* or sensitiv*):ti,ab
#19[mh "Infant Food"]
#20(formula* or bottle next fed* or bottlefed* or bottlefeed* or bottle next feed*):ti,ab
#21[mh Hydrolysis]
#22(hydrolys* or hydrolyz*):ti,ab
#23[mh Prebiotics]
#24[mh ^"Amino acids"]
#25(amino next acid* or aminoacid* or casein* or fibre* or fiber* or prebiotic* or pre next biotic* or soy* or whey*):ti,ab
#26[mh "Dietary Proteins"]
#27[mh "diet therapy"/FS]
#28diet*:ti,ab
#29[mh "Dairy Products"]
#30[mh Fishes]
#31[mh Eggs]
#32[mh Gluten]
#33[mh Nuts]
#34(cheese* or dairy or egg* or fish* or gluten* or wheat* or nut* or peanut* or lactose* or yogurt* or yoghurt*):ti,ab
#35{or #10-#34}
#36 #9 and #35 in Cochrane Reviews (Reviews and Protocols)
Database of Abstracts of Reviews of Effects (DARE), part of the Cochrane Library
#1[mh Colic]
#2colic*:ti,ab
#3[mh Crying]
#4(cry or crying or cries):ti,ab
#5{or #1-#4}
#6[mh Infant]
#7(baby or babies or child* or infant* or newborn* or neonate*):ti,ab
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#8{or #6-#7}
#9#5 and #8
#10[mh Milk]
#11[mh "Milk, Human"]
#12[mh "Breast Feeding"]
#13(breastfeed* or "breast feed*" or breastfed or "breast fed" or breastmilk* or "breast milk*" or milk*):ti,ab
#14[mh ^Hypersensitivity]
#15[mh "Food Hypersensitivity"]
#16[mh ^Allergens]
#17[mh "Lactose Intolerance"]
#18(allerg* or hypoallerg* or hypo next allerg* or hyperallerg* or hyper next allerg* or hypersensitiv* or hyper next sensitiv* or intoleran*
or non next allerg* or nonallerg* or sensitiv*):ti,ab
#19[mh "Infant Food"]
#20(formula* or bottle next fed* or bottlefed* or bottlefeed* or bottle next feed*):ti,ab
#21[mh Hydrolysis]
#22(hydrolys* or hydrolyz*):ti,ab
#23[mh Prebiotics]
#24[mh ^"Amino acids"]
#25(amino next acid* or aminoacid* or casein* or fibre* or fiber* or prebiotic* or pre next biotic* or soy* or whey*):ti,ab
#26[mh "Dietary Proteins"]
#27[mh "diet therapy"/FS]
#28diet*:ti,ab
#29[mh "Dairy Products"]
#30[mh Fishes]
#31[mh Eggs]
#32[mh Gluten]
#33[mh Nuts]
#34(cheese* or dairy or egg* or fish* or gluten* or wheat* or nut* or peanut* or lactose* or yogurt* or yoghurt*):ti,ab
#35{or #10-#34}
#36#9 and #35 in Other Reviews
LILACS (Latin American and Caribbean Health Science Information Database; search.bvsalud.org/portal/?lang=en)
tw:((colic* OR cries OR crying OR cry) AND (infant* OR newborn* OR neonate* OR baby OR babies OR child*)) AND (instance:"regional")
AND ( db:("LILACS") AND type_of_study:("clinical_trials"))
IBECS (search.bvsalud.org/portal/?lang=en)
(tw:(colic* OR cries OR crying OR cry)) AND (tw:(infant* OR newborn* OR neonate* OR baby OR babies OR child*)) AND (instance:"regional")
AND ( db:("IBECS")) AND (instance:"regional") AND ( type_of_study: ("clinical_trials"))
HomeoIndex (bases.bireme.br/cgi-bin/wxislind.exe/iah/online)
Search on : colic$ or cry$ or cries [Words] and infant$ [Words]
Networked Digital Library of Theses and Dissertations (NDLTD; www.ndltd.org)
infant* AND colic AND random*
TROVE (limited to Australian theses; trove.nla.gov.au)
Keyword: Any of the words: infant* babies
Keyword: Any of the words: colic* crying
Keyword: Any of the words: random* placebo* control* blind* group*
Limited to Books Format: Thesis
WorldCat OCLC (limited to theses; www.worldcat.org)
(ti:infant* OR babies) AND (kw:colic* OR crying) AND (kw:random* OR trial* OR control* OR blind*)
PubMed Diet Supplement subgroup (ods.od.nih.gov/Research/PubMed_Dietary_Supplement_Subset.aspx)
#26 (#22 and #25) Filters: Dietary Supplements
#25 (#23 or #24) Filters: Dietary Supplements
#24 (baby [tiab] or babies [tiab] or child* [tiab] or infant [tiab] or newborn [tiab] or neonate [tiab]) Filters: Dietary Supplements
#23 infant [mh] Filters: Dietary Supplements
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#22 (#9 and #21) Filters: Dietary Supplements
#21 (#18 NOT #20) Filters: Dietary Supplements
#20 ((animals [mh] NOT humans [mh])) Filters: Dietary Supplements
#18 (#10 or #11 or #12 or #13 or #14 or #15 or #16 or #17) Filters: Dietary Supplements
#17 groups [tiab] Filters: Dietary Supplements
#16 trial [tiab] Filters: Dietary Supplements
#15 randomly [tiab] Filters: Dietary Supplements
#14 drug therapy [sh] Filters: Dietary Supplements
#13 placebo [tiab] Filters: Dietary Supplements
#12 randomized [tiab] Filters: Dietary Supplements
#11 controlled clinical trial [pt] Filters: Dietary Supplements
#10 randomized controlled trial [pt] Filters: Dietary Supplements
#9 (#1 or #2 or #5 or #6 or #7 or #8) Filters: Dietary Supplements
#8 (crying[tiab] or cry [tiab] or cries [tiab]) Filters: Dietary Supplements
#7 crying [mh] Filters: Dietary Supplements
#6 ((spasm* [tiab] or pain* [tiab] or cramp* [tiab])) AND (gastro* [tiab] or gastric[tiab]) Filters: Dietary Supplements
#5 (((spasm* [tiab] or pain* [tiab] or cramp* [tiab]))) AND ((stomach[tiab] or abdominal [tiab] or abdomen* [tiab]) Filters: Dietary
Supplements
#2 colic* [tiab] Filters: Dietary Supplements
#1 colic [mh] Filters: Dietary Supplements
ClinicalTrials.gov (clinicaltrials.gov)
infant colic AND Study type= intervention
World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; apps.who.int/trialsearch)
Basic search infant* AND crying OR infant* AND cries OR infant* AND colic*
Appendix 2. 'Risk of bias' criteria and judgements
Sequence generation for randomisation
We included only RCTs or quasi-RCTs in this review. We assessed randomisation at low risk of bias if the procedure of sequence generation
was explicitly described. Examples include computer-generated random numbers, a random numbers table or coin-tossing. Where no
description was given, we contacted the study authors for further information, and where we failed to receive a response, we assigned a
judgment of unclear risk of bias. We considered studies to be at high risk of bias when reporting methods that were not random.
Allocation concealment
We assessed concealment of treatment allocation at low risk of bias if the procedure was explicitly described and adequate efforts
were made to ensure that intervention allocations could not have been foreseen in advance of, or during, enrolment. Examples include
centralised randomisation, numbered or coded containers, or sealed envelopes. We considered the following procedures to have a high
risk of bias: alternation, or reference to case record numbers or dates of birth. Where no description was given, we contacted the study
authors and, if we did not receive a response, we assigned a judgment of unclear risk of bias.
Blinding of parents and health professionals
In this context, the intervention is administered by parents and so, in effect, we considered them to be the target of the blinding procedures.
Indeed, as the participants were less than four months of age by the defined inclusion criteria (Criteria for considering studies for this
review), we deemed that this item was not applicable to them. Furthermore, parents often act as outcome assessors. We primarily assessed
the risk of bias associated with the blinding of participants based on the likelihood that such blinding was sufficient to ensure that parents
had no knowledge as to which intervention the infant received. We assessed blinding at low risk of bias where it was explicitly described
how the parents could have no knowledge of which intervention the infant was receiving, and at high risk of bias where it was clear that
parents were aware of which intervention the infant was receiving. We assessed blinding at unclear risk of bias where we did not have
enough information to make an assessment of either high or low risk of bias, based on the information provided in the papers, or after
contacting the study authors.
Blinding of outcome assessment
For each included study we described the methods used, if any, to blind the outcome assessors from knowledge of which intervention
a participant received. We judged studies at low risk of bias if they were blinded, or if we considered that the lack of blinding could not
have affected the results. If blinding was not possible because of the nature of intervention, we judged the study at high risk of bias since
it is possible that the lack of blinding influenced the results. We noted the blinding of health professionals where reported. Where no
description was given, we contacted the study authors for more information, and where we did not receive a response, we assigned a
judgment of unclear risk of bias.
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Incomplete outcome data
Incomplete outcome data essentially include attrition, exclusions, and missing data.
We assigned a judgment of low risk of bias if:
1. participants included in the analysis were exactly those who were randomized into the trial, if missing outcome data were balanced in
terms of numbers across intervention groups, with similar reasons for missing data across groups, or if there were no missing outcome
data;
2. for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was not sufficient to have a
clinically relevant impact on the intervention effect estimate;
3. for continuous outcome data, the plausible effect size (SMD) among missing outcomes was not sufficient to have a clinically relevant
impact on observed effect size; or
4. missing data were imputed using appropriate methods.
We assigned a judgment of high risk of bias:
1. when reasons for missing outcome data were likely to be related to the true outcome, with either an imbalance in numbers or reasons
for missing data across intervention groups;
2. for dichotomous outcome data, when the proportion of missing outcomes compared with observed event risk was sufficient to induce
clinically relevant bias in the intervention effect estimate;
3. for continuous outcome data, when the plausible effect size (SMD) among missing outcomes was sufficient to induce clinically relevant
bias in the observed effect size;
4. when an 'as-treated' analysis was carried out in cases where there was substantial departure of the intervention received from that
assigned at randomisation; or
5. when there was a potentially inappropriate application of simple imputation.
We assigned a judgment of unclear risk of bias:
1. when there was insufficient reporting of attrition or exclusions (or both) to permit a judgment of low or high risk of bias;
2. if the study reported incomplete outcome data; or
3. if the numbers randomized to intervention and control groups were not clearly reported.
Selective outcome reporting
We assessed the reporting of outcomes at low risk of bias if all study outcomes declared in the Methods section were reported in the Results
section. We also evaluated whether different reports of the study were available, including protocols, and examined them to ensure there
was no suggestion of selective outcome reporting. Where no description was given, we contacted the study authors for more information,
and where no response was received, we assigned a judgment of unclear risk of bias. Where there was evidence of selective outcome
reporting, we assigned a judgment of high risk of bias.
Other potential threats to validity
Where a study was at risk of other sources of bias, we assessed it at high risk of bias. For instance, sources of sponsorship or funding
constitute one common example of a factor which may pose a risk of bias. We assessed each study at low risk of bias if it appeared to be
free from such threats to validity. Where the risk of bias was unclear from the published information, we attempted to contact the study
authors for clarification. Where this information was not forthcoming, we assessed these studies at unclear risk of bias.
WHAT'S NEW
Date
Event
Description
28 February 2019
Amended
This review has been revised to clarify reporting of data in summary versions.
1 November 2018
Amended
Typo corrected in Plain Language Summary.
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CONTRIBUTIONS OF AUTHORS
Morris Gordon wrote the protocol (Savino 2014), organised retrieval of papers, wrote to study authors for additional information, supported
the search, extracted and analysed data, wrote the core text of the review, and led revisions of the draft.
Elena Biagioli wrote the protocol and reviewed the Results section of the review.
Miriam Sorrenti wrote the protocol and the Discussion section of the review.
Carla Lingua added references and supported the search.
Lorenzo Moja provided statistical advice and revised key sections of the review.
Shel Banks organised retrieval of papers, wrote to study authors for additional information, supported the search, extracted and analysed
data, and wrote the review.
Simone Ceratto wrote the Discussion section and contributed to the write-up of the Results section of the review.
Francesco Savino has primary responsibility for the review. He co-ordinated the efforts of the review authors. He wrote the protocol and
contributed to the write-up of the Results and Discussion sections of the review.
DECLARATIONS OF INTEREST
Morris Gordon (MG) received travel grants from a number of companies during the three years leading up to publication, including from
Allergan, Ferring Pharmaceuticals, Biogaia, Synergy and Tillots, to attend conferences (Advances in Inflammatory Bowel Disease, Digestive
Disease Week, World Congress of Gastroentrology) and present the results of other Cochrane Reviews. These companies have had no input
or involvement in any aspect of the review process during this, or previous systematic reviews carried out by MG. MG currently holds a
National Institute for Health Research (NIHR) Cochrane Programme Grant, although this did not support this work. MG is a paediatrician
with an interest in gastroenterology. This involves seeing patients referred with infantile colic and managing their condition in line with
current, accepted, evidence-based practice. MG has no other interests to declare.
Elena Biagioli – none known.
Miriam Sorrenti – none known.
Carla Lingua – none known.
Lorenzo Moja – none known.
Shel Banks (SB) is self-employed as an Internationally Board Certified Lactation Consultant in private practice, delivering expertise in infant
feeding evidence base, writing briefing papers and newsletters, etc., and delivering workshops across the northwest of England – largely for
the Local Infant Feeding Information Board (LIFIB), but also the Sudden Unexpected Death of a Child (SUDC) prevention team, Lanacshire.
Until March 2016, the SUDC consultant post was funded by the local authority (Lancashire County Council) via breastfeeding voluntary
sector charity (Breastfeeding Network) and SB was paid by the hour. SB is also self-employed as a trainer and webinar presenter ad hoc and
delivers Babyem's Open College Network Level Three and Four Maternity Nurse Training courses. Since 2009, SB has worked part-time as a
Baby Friendly Co-ordinator, and she was paid for 12 months by Blackpool Teaching Hospitals NHS Foundation Trust as a Research Assistant
for her work on this review. SB is Chair of LIFIB, Chair of the Communications Team, Chair of the Breastfeeding Festival, Committee Member
of the Lactation Consultants of Great Britain, and a Trustee of the UK Association of Milk Banking, all of which are voluntary positions,
although SB's travel expenses to meetings are paid. SB received travel expenses from Manchester City Council for speaking at their event
'Make Manchester a Breastfeeding Friendly City' in June 2018. SB has sat as a lay member on the Guideline Development Committee
of three NICE Guidelines (Milk Banking, Postnatal Care Quality Standards and Faltering Growth), and was paid an honorarium by NICE
(National Institute for Health and Care Excellence) for her services. SB declares that neither she personally, nor any of the entities she
represents, take funding of any kind from any commercial interests in infant feeding or early years, and that she works completely within
the professional code of ethics as an Internationally Board Certified Lactation Consultant. SB has no other interests to declare.
Simone Ceratto (SC) received travel grants from Nóos S.r.l and Nestlé, to attend scientific meetings. SC declares that he attended 'Campus
Angelini 2017', which was sponsored by Angelini.
Francesco Savino (FS) received payment from: Danone Nutricia Middle-East DMCC, Dubai, United Arab Emirates, and Innova Pharma SpA
Recordati SpA, Milan, Italy, for talks at symposiums; Società Italiana di Pediatria, Milan, Italy, for speaking at the XX Congresso Nazionale
SIAIP, sponsored by Biomedia srl, Milan; HiPP GmbH & Co, Vertrieb KG, Pfaffenhofen, Germany, for consultancy work; and from Aretrè
srl, Milan, Italy, for development of educational materials, outside the submitted work. FS also received a travel grant from Noos Roma,
Italy, to attend ESPGHAN's 51st Annual Meeting, Geneva, and receives royalties from Springer Verlag, Milan, Italy, for the book Nutrizione
Parenterale in Pediatria. FS declares that these organizations have had no input or involvement in any aspect of the review process during
this, or previous systematic review that he has carried out. FS has no other interests to declare.
Disclaimer: the views contained herein are those of the authors and not necessarily those of the Department of Health, NHS NICE or NIHR.
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SOURCES OF SUPPORT
Internal sources
• Department of Pediatrics, Regina Margherita Children's Hospital, Città della Salute e della Scienza, Turin, Italy.
Logistical support
External sources
• None, Other.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
Please see our protocol (Savino 2014).
Authors
Valentina Tarasco left the review team and was replaced by Shel Banks and Simone Ceratto.
Morris Gordon took over as lead author.
Types of outcome measures
We reworded the outcomes of 'reduction in the duration of crying' and 'reduction in frequency of crying episodes per 24 h, to the following
more neutral formulations, to reflect the fact that we are assessing the variable rather than a reduction in the variable: 'duration of crying'
and 'frequency of crying episodes per 24 h'.
We planned on defining responders as a 50% reduction in crying. However, the peer reviewers raised questions as to the external basis for
this decision, so we decided to revert to a more standard definition of 'responders', as defined by primary studies. As no study reported
outcomes in this area with utility for analysis, this did not impact the analysis or findings.
Originally, we planned on reporting only change scores for the primary outcome; however, many studies reported only postintervention
data, and so we decided to include these too.
We planned further analyses according to each specific adverse effect when the primary studies provided sufficient data. However, we did
not complete this analysis as such data were not presented, with adverse effects rarely encountered.
In addition, we included the outcome 'parental satisfaction' in Summary of findings for the main comparison, but this was not in our
protocol (Savino 2014). We modified the Methods sections accordingly.
See Types of outcome measures.
Search methods for identification of studies
In order to ensure our search was as up-to-date as possible, we searched two additional databases, which are updated daily (Ovid MEDLINE
In-Process & Other Non-Indexed Citations and Ovid MEDLINE Epub Ahead of Print). See Electronic searches.
Selection of studies
We clarified that we excluded stand-alone abstracts from this review. Given the extreme complexity of the studies found, including issues
of heterogeneity of specific interventions, patient characteristics and outcomes reported, as well as the poor quality of the abstracts found
within the search, the team decided not to consider abstracts unless they related to a study for which we also had a full-text report. See
Selection of studies.
Measures of treatment effect:
Dichotomous data
We planned to present dichotomous outcome data as risk ratios (RR), since the effects of the RR are readily understood (Walter 2000). We
report all outcome data with their associated 95% CIs and P values (where possible). Using control event risks from the included trials,
we planned to calculate the number needed to treat to benefit (NNTB) and its associated 95% CI for statistically significant dichotomous
outcomes.
Continuous data
If all studies used the same measurement scale, we intended to calculate the mean difference (MD) for change scores. Where studies used
different scales, we planned to calculate the standardised mean difference (SMD) using Hedges' g. Where necessary, we calculated effect
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estimates from P values, t statistics, analysis of variance (ANOVA) tables or other statistics, as recommended in the Cochrane Handbook for
Systematic Reviews of Interventions (Deeks 2017).
To analyse continuous data, we planned to use, according to need, either change scores or final values without combining them. However,
no such analysis was possible due to a lack of data.
Had both continuous and dichotomous data been available for an outcome, we planned to include only the continuous outcome in the
primary analysis. We planned that when studies had reported an outcome as a dichotomous measure, and others had used a continuous
measure of the same construct, to convert the results for the former from the dichotomous measure to a standardised mean difference,
provided that we could assume the underlying continuous measure had an approximately normal or logistic distribution (otherwise we
would have carried out two separate analyses). However, no such analysis was possible due to a lack of data. See Measures of treatment
effect.
Unit of analysis issues
Studies with multiple treatment arms
Had our strategy to combine data to make single, pair-wise comparisons prevented investigation of potential sources of heterogeneity,
we planned to analyse each formula separately (against a common control group – placebo), but divide the sample size for common
comparator arms proportionately across each comparison (Higgins 2011b). This simple approach allows the use of standard software
(including RevMan 2014), and prevents the inappropriate double-counting of individuals; however, it was not needed due to a lack of data.
Additionally, concerns with the length of a reasonable washout period existed and further limited scope for such analysis.
Cross-over studies
For cross-over trials, we planned to used the mean and standard error of the paired analysis for the meta-analysis; however, this was not
possible due to a lack of data. In future updates of this review, should we have sufficient data, we will include both parallel and cross-over
studies with an adequate washout period in a meta-analysis using the inverse variance method, as recommended by Elbourne 2002; in
the meta-analysis, the weight of each study is inversely proportional to the variance (one over the square of the standard error) (Deeks
2017). We will include cross-over studies with an inadequate washout period in a meta-analysis using the data from the first arm only. Even
though this method excludes some of the data, it avoids the inappropriate consideration of correlated information.
See Unit of analysis issues.
Dealing with missing data
For all outcomes in all studies, we planned to carry out analyses as far as possible on an intention-to-treat basis; that is, we planned to
attempt to include all participants randomised to each group in the analyses, and we analysed all participants in the group to which they
were allocated regardless of whether or not they received the allocated intervention. For missing continuous data, we intended to estimate
standard deviations from other available data, such as standard errors, or impute them using the methods suggested in Higgins 2011b. For
loss to follow-up for continuous data, we planned to base analyses on those participants completing the trial, essentially assuming that
outcome was the same in the missing participants and the observed participants. Where there was a discrepancy between the number
randomised and the number analysed in each treatment group, we intended to calculate and reported the percentage lost to follow-up in
each group. We planned to explore the impact of including studies with high levels of missing data in the overall assessment of treatment
effect by conducting sensitivity analyses (see Sensitivity analysis).
Data synthesis
Where interventions were similar in terms of type of dietary modification, type of outcome assessed and type of colic, we planned to
group studies and synthesised their results in a meta-analysis. Because we assumed that clinical heterogeneity was very likely to impact
on our results, given the wide breadth and types of interventions included, we intended to combine studies using a random-effects model,
irrespective of statistical evidence of heterogeneity. We planned to calculate all overall effects using inverse variance methods and carried
out statistical analysis using RevMan 5 (RevMan 2014).We included a new section on 'Assessment of the quality of the evidence' at the
request of the editorial base. See Data synthesis.
Assessment of heterogeneity
We planned to assess statistical heterogeneity by examining the I2 statistic (Deeks 2017), a quantity that describes the proportion of
variation in point estimates that is due to variability across studies rather than sampling error. We interpreted the I2 statistic as suggested
in the latest version of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2017).
1.
2.
3.
4.
0% to 40%: might not be important.
30% to 60%: may represent moderate heterogeneity.
50% to 90%: may represent substantial heterogeneity.
75% to 100%: considerable heterogeneity.
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We also evaluated the CI for the I2 statistic. In addition, we employed a Chi2 test of homogeneity, with a 10% level of significance, to
determine the strength of the evidence that the heterogeneity was genuine.
Subgroup analysis and investigation of heterogeneity
Large numbers of subgroup analyses may lead to misleading conclusions (Oxman 1992; Yusuf 1991). We planned to conduct the following
subgroup analyses,
1.
2.
3.
4.
5.
Age of mother at time of birth (21 years and younger versus older than 21 years).
Type of feeding (formula-fed versus breastfed).
Atopy (lower versus higher risk of atopy).
Follow-up (less than four weeks of treatment versus more than four weeks of treatment).
Trial quality (low quality (lack of allocation concealment or lack of blinding) versus high quality (allocation concealment and blinding)).
Sensitivity analysis
We planned to conduct sensitivity analyses to determine whether findings were sensitive to restricting the analyses to studies judged to
be at low risk of bias for blinded assessment of the primary outcome. In addition, we planned to assess the sensitivity of findings to any
imputed data, by calculating the treatment effect including and excluding the imputed data, to see whether this altered the outcome of
the analysis. We planned to investigate the effect of dropouts and exclusions by conducting worst- versus best-case scenario analyses. We
analysed the effect of using the stringent Wessel 1954 definition of infant colic, the more recent definition given by Drossman 2016 and
other variants.
Additional references
We updated our references to the latest versions of Chapters 8, Higgins 2017, and 9, Deeks 2017, in theCochrane Handbook for Systematic
Reviews of Interventions.
INDEX TERMS
Medical Subject Headings (MeSH)
*Infant Formula; Allergens; Colic [*diet therapy]; Crying; Diet Therapy [methods]; Lactase [administration & dosage]; Randomized
Controlled Trials as Topic; Soybean Proteins [administration & dosage]; Time Factors
MeSH check words
Female; Humans; Infant; Male
Dietary modifications for infantile colic (Review)
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