Table 1 Summary of the included reviews

Perry UK [22]

RCTs, children diagnosed with IC (e.g. Wessel), any form of CAM versus placebo, no treatment, TAU or WL as control groups

5 databases from inception to February 2010

No language/date restrictions

Grey literature not searched

Supplements, herbal, massage, reflexology, manipulation, mixed treatment

RCTs with the following primary outcomes: subjective measures of colic severity in parental self- report/observer completed QoL parameters; in physiologic parameters; reduction in the need for medication, other treatment or adverse effects of treatment (from BL)

No: No

Jadad score: Yes

Some encouraging results exist for fennel extract, mixed herbal tea and sugar solutions, although all trials have major limitations. Thus, the notion that any form of CAM is effective for infantile colic currently is not supported from the evidence from the included RCTs. Additional replications are needed before firm conclusions can be drawn.

Bruyas-Bertholon [23]

France

RCTs or MAs

Therapeutic evaluation of colic or excessive crying in infants < 6 mths

3 databases to December 2010

French and English papers only

Grey literature not searched

Non-allopathic drug, manual therapies, soy

NR

No: No

Jadad score: Some trials reported AEs

The main therapeutic strategies currently validated are, fennel herbal medicine and the probiotic L. reuteri. It seems reasonable to combine reassurance and healthy lifestyle counselling with parents, and a limitation of stimulation around the child. These results could serve as a basis for a consensus conference on the management of infant colic.

Harb [24]

Australia

RCTs (incl. crossover), published after 1 January 1980

The ppts were mothers of colicky fully or partially breast-fed infants < 6 mths

Wessel (incl. modified)

Excluded if the sample size was < 16 ppts

5 databases searched from July 2014?? to 31 July, 2015

Grey literature not searched

Probiotic/symbiotic, phytotherapies (NB: other therapies included but not relevant to our report)

Changes in crying duration, response rates as measured by a reduction in symptoms

Yes: Yes

Cochrane RoB: No

Probiotics, in particular, L. reuteri, and preparations containing fennel oil appear effective for reducing colic, although there are limitations to these findings. The evidence for sucrose, glucose, is weak. Further well-designed clinical trials are required to strengthen the evidence for all of these interventions.

Gutierrez-Castrellon [25]

Mexico

RCTs, published between 1960 and 2015 for the treatment of IC

Search between January 1960 and August 2015 in 7 databases and databases of the principal international regulatory agencies

English or Spanish language only. Grey literature not searched

Probiotics, Soy, herbal, acupuncture, manipulation, massage

duration of crying after 21 to 28 days of treatment

Yes, alongside Network meta-analysis; No

Yes: Cochrane ROB (not reported for each trial): partial reporting of AEs

Based on systematic analysis of evidence and networking meta-analysis approach use of L. reuteri DSM17938 seems to be the most evidence-based significant intervention to reduce the duration of crying time in infantile colic. The associated evidence for the use of other interventions such as, herbals, acupuncture, or spinal massage is reduced or significantly biased to let us recommend as potential interventions.

Dobson [26]

UK

Cochrane review

RCTs, infants < 6 mths, assessed by clinicians as suffering from colic (all unexplained crying were accepted)

Searched 11 databases, conference proceedings, and trials registries.

In addition, CentreWatch, NRR Archive and UKCRN were search in December 2010

Chiropractic, osteopathy or cranial osteopathy alone or in conjunction with other interventions

1. Change in hours crying time per day (post-treatment versus BL)

2. Presence/absence of colic after treatment or FU, or both, that is, the number of infants in which excessive crying resolved (using the definition of those conducting the trial)

3. Any reported AEs, e.g. injury, stroke, arterial dissection, worsening of symptoms

Yes: Yes

Cochrane ROB: Yes

The majority of the included trials appeared to indicate that the parents of infants receiving manipulative therapies reported fewer hours crying/day than parents whose infants did not, based on contemporaneous crying diaries, and this difference was statistically significant. The trials also indicate that a greater proportion of those parents reported improvements that were clinically significant.

However, most studies had a high risk of performance bias due to the fact that the assessors (parents) were not blind to who had received the intervention. When combining only those trials with a low risk of such performance bias, the results did not reach statistical significance. Further research is required where those assessing the treatment outcomes do not know whether or not the infant has received a manipulative therapy. There are inadequate data to reach any definitive conclusions about the safety of these interventions.

Gleberzon [27]

Canada

Human pptss aged ≤ 18

Involve 2+ ppts,

treatments administered

by a chiropractor; prospective or retrospective studies, studies using an outcome measure for determining the effect of chiropractic care

2 databases published between January 1980 and March 2011

Papers were written in English and published in peer-reviewed journal

Manual HVLA thrusting

spinal manipulations

Effectiveness of SMT on colic (alongside other conditions)

No: No

Sackett 1999 quality grading:

Yes

Studies that monitored both subjective and objective outcome measures of relevance to both patients and parents tended to report the most favourable response to SMT, especially among children with asthma. Many studies reviewed suffered from several methodological limitations. Further research is clearly required in this area of chiropractic health care, especially with respect to the clinical effectiveness of SMT on paediatric back pain.

Carnes [28]

UK

RCTS, case series, cohorts, service evaluation, qualitative studies.

Participants aged 0 mths and 12 mths (infants) when received treatment.

Healthy, thriving and not receiving other medical interventions,

Wessel criteria

9 databases searched from 1990 (date restriction due to update), including peer networks. Grey literature was searched

Where the manual therapy intervention was delivered in primary care by statutorily registered or regulated professional(s)

Unsettled behaviours (including excessive crying, lack of sleep, displays of distress or discomfort (back arching and drawing up of legs) and difficulty feeding.

Experience/satisfaction and global change scores.

Adverse events

Yes: No

Cochrane RoB: Yes

Some small benefits were found, but whether these are meaningful to parents remains unclear as does the mechanisms of action. Manual therapy appears relatively safe.

Skejeie [29]

Norway

Completed RCTs; Wessel criteria (+ modified); no exclusion criteria

9 databases (4 Chinese databases) were searched up to February 2017 alongside 1 trial register

Percutaneous needle acupuncture

Chane from BL crying time at mid and end point, and month FU

A 30-min MD in crying time between acupuncture and control was predefined as a clinically important difference

Yes: Yes

Cochrane RoB: Yes

Percutaneous needle acupuncture treatments should not be recommended for infantile colic on a general basis.

Anheyer [30]

Germany

RCTs comparing herbal therapy with no treatment, placebo, or medication in children and adolescents (aged 0–18 years) with GI disorders

3 databases were searched through to July 15, 2016.

English and German language only.

Different herbal

treatment options (homoeopathic form or Chinese medicine were excluded)

NR

Yes: No

Cochrane RoB: Yes

Because of the limited number of studies, results have to be interpreted carefully. To underpin evidence outlined in this review, more rigorous clinical trials are needed.

Sung [31]

Australia

RCTs,

<  3 mths at start of oral probiotic supplementation vs placebo, standard care or no care, any probiotic given to either mothers or infants in both term and preterm infants

Wessel criteria of colic

3 databases from 1950 to June 2012 limited to ‘all infants (birth to 23 mths)’ plus 2 trials registers

non-English language and unpublished data were excluded

Probiotics

Infant crying, measured as the duration or number of episodes of infant crying/distress, or diagnosis of infant colic (Wessel criteria)

Yes: No

Cochrane RoB: No

Although L. reuteri may be effective as treatment for crying in exclusively breastfed infants with colic, there is still insufficient evidence to support probiotic use to manage colic, especially in formula-fed infants, or to prevent infant crying. Results from larger rigorously designed studies applicable to all crying infants will help draw more definitive conclusions.

Anabrees

[32]

Saudi Arabia

RCTs or quasi-RCTs, comparing probiotics to placebo, control or other treatment, term healthy infants with colic,

< 4 mths old

3 databases plus contacted experts

No language restriction (but abstracts needed to be in English)

L. reuteri DSM 17938 or L. reuteri ATCC 55730

treatment success, defined as the % of children who achieved a reduction in the daily average crying time > 50%.

Yes: Yes

Cochrane RoB: No

Although L. reuteri may be effective as a treatment strategy for crying in exclusively breastfed infants with colic, the evidence supporting probiotic use for the treatment of infant colic or crying in formula-fed infants remains unresolved. Results from larger rigorously designed studies will help draw more definitive conclusions.

Urbanska [33]

Poland

RCTs, children aged 0 to 18 years, trials to compare L. reuteri DSM 17938 with placebo or no intervention, not just colic included

2 databases searched to April 2014,

2 trials registers

No language restrictions. Grey literature not searched

L. reuteri DSM 17938

NR

Yes: Yes

Cochrane RoB: Yes

Our results precisely define current evidence on the effects of the administration of L. reuteri DSM 17938 to the paediatric population.

Xu [34]

China

RCTs;

Aged 3–6 mths

Colic diagnosis (Wessel’s criteria)

Not excluded if infants have allergy to milk protein or a family history of allergy

7 databases were searched to May 2015. Conference abstracts excluded.

L. reuteri DSM 17938

Treatment effectiveness (defined as % of children achieving a ≥ 50% reduction in daily average crying time); duration of crying (min/day)

Yes: Yes

Cochrane RoB: Yes

Lactobacillus reuteri possibly increased the effectiveness of treatment for infantile colic and decreased crying time at two to three weeks without causing adverse events. However, these protective roles are usurped by gradual physiological improvements. The study is limited by the heterogeneity of the trials and should be considered with caution. Higher quality, multicenter randomised controlled trials with larger samples are needed.

Schreck Bird [35]

USA

RCTs

Any probiotic compared to placebo or simethicone

Administered to term infant with colic

4 databases from 1947 to December 2014.

English language & published trials only.

L. reuteri DSM 17938 or

L. reuteri ATCC 55730

assessing crying or fussing time

Yes: No

Cochrane RoB: Yes

Supplementation with the probiotic L. reuteri in breastfed infants appears to be safe and effective for the management of infantile colic. Further research is needed to determine the role of probiotics in infants who are formula-fed.

Dryl [36]

Poland

RCTs, efficacy of probiotics (any well-defined strain) compared with placebo

2 databases searched up to April 2016. Grey literature not searched

Probiotics (any well-defined strain)

Treatment success

The duration of crying at the end of the intervention

Yes: Yes

Cochrane RoB: No

Some probiotics, primarily L. reuteri DSM 17938, may be considered for the management of infantile colic. Data on other probiotics are limited.

Sung [37]

Australia

DB RCTs (published by June 2017)

L. reuteri DSM17398 versus a placebo, delivered orally to infants with colic

6 databases and e-abstracts, and clinical trial registries

L. reuteri DSM17398

Infant crying and/or fussing duration; treatment success at 21 days

Yes (IPD): Yes

Cochrane RoB: No

L. reuteri DSM17938 is effective and can be recommended for breastfed infants with colic. Its role in formula-fed infants with colic needs further research.