A subgroup meta-analysis of MDs in crying times for the probiotic L reuteri was performed on data at 21 days of treatment (Fig. 2), because this was the common data collection point for these studies. Overall, L reuteri reduced crying time in the infants studied (pooled MD −55.9 min/day, 95% CI −64.4 to −47.3, P < 0.001) (Figure 2).
The study by Kianifar et al (44) examined the effects of a synbiotic mixture that contained 6 species of microbiota (Lactobacillus casei, Lactobacillus acidophilus, Bifidobacterium. infantis, Lactobacillus bulgaricus, Lactobacillus rhamnossus, Streptococcus thermophilus, Bifidobacterium breve) plus fructo-oligosaccharide, and despite the availability of crying data pre and post intervention, it was not included in the subgroup meta-analysis because the preparation did not contain L reuteri and was considered not directly comparable to the studies using L reuteri.
Preparations Containing Fennel
A subgroup meta-analysis was conducted on the 3 studies testing the efficacy of fennel on reducing crying time in infants (Fig. 3). Overall, preparations containing fennel demonstrated effectiveness with a pooled MD of −72.1 min/day (95% CI −126.4 to −17.7, P < 0.01). The Alexandrovich et al (42) study included 125 infants of 2 to 12 weeks, with response rates and cumulative crying being the reported outcomes. The authors reported response to treatment rates for 65% of infants, whereas 23.7% also responded to the placebo, demonstrating a significant placebo effect in this study.
Arikan et al (41) studied 4 intervention groups and a control group with no intervention. Infants in treatment group 3 (n = 35) were given tea containing fennel. Baseline mean crying time for the fennel tea group was 306.6 min/day (±85.8), and at the end of the intervention it had reduced to 192.0 min/day (±73.8). When compared with the other 2 studies in this subgroup meta-analysis, the MD was −109.2 min/day (95% CI −219.1 to 0.7, P = ns). Because of the large confidence interval and it crossing the line of no effect, the study was, however, considered of limited value.
Savino et al 2005 (45) examined the effects of a commercially available phytotherapeutic agent containing fennel (ColiMil), with simethicone used as the comparator (n = 88). The study outcomes were reported as crying durations and response rates. Mean crying duration at baseline in the treatment group was 201.2 min/day (±18.3), reducing to 76.9 min/day (±23.5) at day 7, equating to a mean reduction of crying of −124.3 min/day (±11.8), P < 0.001. This study reported a response rate in the treatment group of 85.4% and 48.9% for the placebo, which is a high placebo response. In the subgroup meta-analysis, the ColiMil containing fennel appeared to be an effective treatment for infant colic, with an MD in crying time of −95.5 min/day, (95% CI −100.9 to −90.2, P < 0.001). ColiMil, however, contains 4 herbal ingredients and it is unclear how much of the preparation's effectiveness was due to the fennel, other ingredients, or the synergistic effect of the combination of the 4 herbal ingredients.
Interestingly, the study by Weizman et al 1993 (47) also found that a herbal tea containing fennel was effective compared with a placebo. It was, however, unable to be included in the subgroup analysis because no crying data at baseline or posttreatment were available.
Low Allergen Maternal Diet
Because only 1 study on maternal diet was included in this review (43), it was, therefore, not possible to conduct a subgroup meta-analysis on the effects of maternal dietary elimination on crying time. The authors, however, reported a greater reduction in cry/fuss time in the maternal low allergen diet group, with an adjusted geometric mean ratio of 0.79 (95% CI 0.63–0.97) over a 48-hour period.
Three studies examined simethicone (17,49,51). The Alves et al (49) and Savino et al (17) studies used simethicone as the control intervention, whereas the Metcalf et al (51) study aimed to determine the effect of simethicone on infant colic. The Metcalf et al (51) study found no significant difference when simethicone was compared with a placebo. Interestingly, the Alves et al study (49) showed no differences in the infant's response to the active treatment (peppermint) when compared with simethicone as the control, demonstrating that the treatment and placebo had similar effect. Savino et al (17) also used simethicone as the control (vs L reuteri), which was found to be of limited use for relieving infant colic. Overall, it appears that simethicone is not an effective treatment for infant colic.
Glucose and Sucrose
Two studies, Arikan et al (41) and Markestad (50), testing the effectiveness of sucrose, and 1 study, Akcam et al (48), testing the effectiveness of glucose, were included. The Arikan et al study (41), a randomised controlled trial, examined the effect of 4 treatments and a control (no intervention), with n = 35 in each group. One treatment arm used a sucrose solution (12% in distilled water), and crying duration in the sucrose group reduced significantly from 342.6 min/day (102.6) to 236.4 min/day (90.6), with an MD of 100.8 min/day (16.8), P < 0.001.
The Markestad study (50) was a small crossover trial study (n = 19), again testing the effectiveness of a 12% sucrose solution. The author reported only response rates, and in the sucrose group this was 63%, which appears to show its effectiveness for reducing infant colic.
Akcam et al (48) tested the effectiveness of glucose for reducing infant colic with a 30% solution in sterile water in a small crossover trial (n = 25). Outcomes were reported as response rates, with 64% responding to the glucose solution and 48% responding to the placebo.
Kanabar et al (52) reported a crossover trial (n = 53), with an intervention period of 10 days duration and included a 5-day washout period. The authors reported outcomes as response rates for both intention to treat (ITT) analysis (26%, 95% CI 12.9–44.4) and for per protocol (PP) analysis for compliant participants (38%, 95% CI 18.8–59.4). The reported reduction in crying duration between the lactase and placebo groups for ITT was 22.4%, P = ns, and for PP 40.4%, P < 0.01.
There was considerable heterogeneity between the studies examined here. In terms of subgroups meta-analyses, heterogeneity was considerable for both probiotics (L reuteri) and tea containing fennel, with I2 = 77.1%, P = 0.001, and I2 = 99.5%, P < 0.01, respectively, albeit much more pronounced for fennel tea; thus random effects models were chosen for these analyses. This was expected because each of the studies within each subgroup analysis considered here differed in many ways, and the limitations will be further discussed in this review.
Publication bias was assessed with a funnel plot (Fig. 4) and was demonstrated in this review, as evidenced by a high level of heterogeneity between studies (53); differences in methodological quality between studies contributing to the funnel plot's asymmetry and publication bias, that is, some studies (41,48,51) examined have been assessed as high risk of bias; 40% of the studies (16,17,19,20,50,51) are presenting as outliers in the funnel plot; and not all studies in this review reporting their findings in a way that was useful for future meta-analyses. Unpublished studies and grey literature were not considered in this review and may partially explain the reason for the obvious publication bias demonstrated here.
This systematic review has achieved its aim of determining the strength of evidence for treatments for infant colic in breast-fed and predominately breast-fed infants younger than 6 months. A range of systematic and literature reviews on treatments for infant colic have been published since 2000 (26,28–37,54). This review differs greatly from these other previously published reviews with respect to its targeted approach. This systematic review was conducted with a narrow set of inclusion criteria, which examined randomised trials of maternal elimination diets, probiotics/synbiotics, over the counter and prescription remedies, and some herbal preparations. Studies were only included if they defined colic as per Wessel or modified Wessel criteria; studies were conducted with 16 or more participants and involved breast-fed infants, mixed-fed infants, or formula-fed infants in which these infants were given the same intervention as the breast- or mixed-fed infants. Some previous reviews did not report their inclusion criteria, or study selection methods (32). Although many reviews limited their investigation to studies defining colic as Wessel or modified Wessel criteria (28,29,31,35,36), some included studies with varying definitions of colic (26,30,33).
With regard to probiotics/synbiotics, our review, with its inclusion of 3 additional studies since previously published meta-analyses of probiotics for treating infant colic (28,36), strengthens the evidence for probiotics/synbiotics in alleviating infant colic, in particular, L reuteri. Several earlier reviews (28,31,32,35,36,54) support this. For example, Sung et al (28) included 3 of the studies that feature in our present review (17,18,20). Their meta-analysis concluded that L reuteri was effective for reducing colic. In a more recent review, Sung (37) concluded that L reuteri appears effective for breast-fed infants only, and that only a subset of colicky infants (no formula feedings and no diagnosis of gastro-oesophageal reflux) may benefit from supplementation with L reuteri, and that it cannot be recommended for formula-fed infants at this time. The authors, however, caution that the studies they examined were potentially affected by bias. Our meta-analysis also supports that L reuteri is effective for the treatment of infant colic, for exclusively breast-fed infants, and, the studies meeting our strict inclusion/exclusion criteria showed low risk of bias. We also, however, found that L reuteri was effective for mixed-fed and formula-fed infants.
Further well-designed studies, with standardised definitions of colic are needed to strengthen the evidence base for colic interventions. Presently, there is significant heterogeneity between studies, and several limitations exist within the intervention studies examined herein.
Limitations of Studies Using Probiotics/Synbiotics
The results of the Sung et al study (19) are contrary to the finding of the others included in this review regarding the usefulness of L reuteri in treating infant colic; this has generated some international controversy. In their original study, Sung et al (19) suggest that their controversial findings may be due to their study having a larger sample size, compared with previous work in this area; atopy and allergy status of the participants; and/or the possibility of regional differences in endemic gut flora. With respect to the latter, regional differences have been found in gut microbiota, correlated with latitude. The Sung et al study (19) was conducted in Australia, whereas the other studies are Italian (17,18), Canadian (15), and Polish (20), and apparent regional differences in gut microbiota may serve to explain Sung et al's findings (19). Interestingly, when we performed a sensitivity analysis, removing the effect of the Sung et al study (19), this made minimal difference to the overall effectiveness for treating infant colic (MD in crying time −56.4 min/day, 95% CI −64.8 to −47.9, P < 0.001). All of the studies of probiotics/synbiotics examined were assessed as low risk for bias.
Limitations of Studies Using Preparations Containing Fennel
Alexandrovich et al (42) offer a possible mechanism of action for the efficacy of fennel oil. The fennel plant contains many biologically active compounds of unknown effect, and these may have a spasmolytic effect on the smooth muscle of the intestine. Although the authors report a 65% response rate in the fennel group, they also report a higher than expected response rate (23.7%) in the placebo group, noting a significant placebo effect in this study. A similar placebo effect was reported in the Weizman et al study (47), in which 26% responded to the placebo, compared with 57% in the fennel group. Interestingly, the response rate for the placebo group of infants in the Savino et al study (45) was even higher at 48.9%, compared with 85.4% in the ColiMil group, again, representing a significant placebo effect. The treatment period in all of these studies using preparations containing fennel was 7 days, and perhaps if the treatment period was longer a greater effect in the treatment group may have been observed.
Consideration of the role of the placebo effect is important, because 5 of the studies examined in our review demonstrated little or no more effect than the placebo they were compared with (19,48,49,51,55). The placebo effect has been widely investigated, and it has been recognised as neurobiological (56,57), meaning that the expectation of a treatment or placebo being effective creates a biological effect. It is feasible that parents with irritable infants will find any treatment or placebo effective because their participation in any investigation may create an expectation. Interestingly, the validity of the placebo effect has been demonstrated in a recently published study by Partty et al (58), in which 2 data collection methods were used to collect crying data, notably, parental interviews, and validated baby diaries. They found that when parents were asked at interview whether their infants had responded to treatment, 87% reported yes, whereas analysis of the baby diaries showed 0% responded to treatment; this demonstrates a very high-perceived difference by the parents.
There were several methodological issues with the studies investigating fennel. Randomisation in the study of Alexandrovich et al (42) was conducted on an individual basis, and allocation methods were not clearly reported. This contributed to the bias risk score of medium. The Arikan et al study (41) was not blinded, and there were several additional aspects of the study that contributed to the overall rating as high risk for bias, for example, allocation was not clearly stated, sample size calculations were not included, and compliance checks were not stated. In the study by Savino et al (45), sample size calculations were not specified, compliance checking was not stated, and the balance of ITT and PP analyses were not clear; these issues contributed to the overall rating of medium risk of bias. Weizman et al (47) methodology was poorly reported and many aspects contributed to an overall rating of medium risk of bias. For example, blinding was stated as double-blind, but very little information on allocation and concealment was reported to substantiate this. Furthermore, a subjective parental colic improvement score was used, which may be problematic considering the placebo effect, and sample size calculations were not reported. Considering all of the studies examining the effects of preparations containing fennel demonstrated methodological issues, and the aforementioned high placebo response demonstrated that any conclusion regarding the effectiveness of fennel must be drawn with caution.
Limitations of Studies Using Low Allergen Maternal Diet
Two studies on maternal dietary interventions were identified to be meeting the inclusion criteria for this review (43,55); however, 1 of these studies also met the exclusion criteria and was removed from the review. Hill et al (55) included both breast-fed and formula-fed infants, but applied different interventions for each group. The formula-fed infants were randomised to receive either hydrolysed formula or a placebo of standard cow's milk formula as their dietary intervention, whereas the breast-fed infants underwent maternal dietary intervention. This study was unable to be included in our review because the data were reported for both groups combined, with no information given separately for breast-fed infants. As such, these authors reported findings for 2 completely different interventions, in 2 different populations, as a combined response rate. Therefore, it was not possible to determine whether maternal dietary intervention was an effective treatment option for reducing infant colic in breast-fed infants with the study of Hill et al (55).
With respect to a study from Hill et al (43), maternal dietary intervention was found to be effective; however, poor compliance with the dietary intervention in the control group was a major limitation. Only 59% of mothers in the control group were compliant with their intervention, the remaining 41% were partially compliant. This may have skewed the control crying data; however, we cannot be certain of how this has affected the results. In addition, the intervention duration of 1 week may not have been sufficient to eliminate maternal allergens from breast milk, because other studies have shown that some allergens may be present in human breast milk for 9 days and beyond post elimination (59–61). It is clear that more well-designed randomised controlled trials of maternal dietary interventions that are of sufficient duration need to be conducted for exclusively breast-fed infants to determine whether this simple noninvasive approach to treating infant colic is effective.
Limitations of Studies Using Lactase
One study investigating lactase, by Kanabar et al (52), was included in this review. Although these authors did not report baseline crying data, they reported a difference in crying times between the treatment and placebo groups. In addition, they reported response rates overall; however, they did not indicate rates for treatment and placebo groups separately, and as such, this study was unable to be included in the overall meta-analysis of any treatment versus placebo. It was included in the narrative section of this review, because it met the inclusion criteria specified by the PICO statement. Although this study was assessed as low risk for bias based on its methodology, the poor reporting of their findings has contributed to insufficient evidence for lactase as an effective treatment for infant colic.
The study of Miller et al (62) also investigated the effectiveness of lactase, however, was excluded because it did not meet the criteria specified by the PICO statement. This study was a small crossover trial (n = 15), with a 7-day intervention period and no washout period. No response rates or differences in crying durations between baseline and at the end of treatment were reported. The results of hydrogen breath testing were, however, reported, and it was found that concentrations of hydrogen in the breath did not differ significantly between the lactase and the control groups, being indicative of a lack of response to treatment. The authors report that no significant difference in crying duration was demonstrated between the lactase group when compared with the placebo group.
Limitations of the Crossover Design Studies
A major limitation with crossover trials is the length of time allocated for any washout period, where inadequate or nonexistent washout periods may cause carry over effects from the initial treatment. Any carryover effects can introduce bias into the study (63,64). Of the 5 crossover trials (48–52), the Kanabar et al study (52) reported a 5-day washout period, the Alves et al study (49) reported a 3-day washout period, and the Metcalf et al study (51) reported a 1-day washout period, which may not have been adequate for the colic to reappear before the second treatment round. Two studies that did not specify a washout period (48,50) involved saccharides, 1 of these studies (50) also repeated the crossover intervention and the author conceded that the nature of this repeated crossover design may have contributed to the findings.
Further well-designed randomised controlled trials or randomised crossover trials with appropriate washout periods are needed to strengthen the evidence for colic interventions. Any future research methodology should seek to address the high levels of heterogeneity within the present body of research for infant colic. This could be achieved by ensuring a standardised definition of colic, which could be based on the internationally agreed Rome III criteria. Data collection methods should also be standardised, this could include the use of validated tools that capture infant crying in real time, either paper-based or in electronic format to ensure consistency of the data, and ease of data collection for mothers participating in research. Also, a consistent approach to measuring the rates of responding infants would ensure less heterogeneity, this could be achieved by researchers reaching consensus on defining what is meant by a “responder” to treatment by standardising the percentage of reduced crying time to either 25% and more or 50% and more, for example. In addition, standardised reporting of crying data in mean minutes per day, with standard deviations, would be useful to assist with comparisons across similar interventions.
With regard to probiotics/synbiotics, more well-designed trials with this L reuteri, particularly in the Southern hemisphere, would be useful in addressing the present controversy surrounding the findings of Sung et al (19), thereby strengthening the emerging body of research.
With regard to future research investigating maternal dietary interventions for colic, heterogeneity can be reduced by ensuring that the infants of participating mothers are exclusive or fully breast-fed, and that the mothers are subject to only 1 intervention, for example, a hypoallergenic diet or another type of diet, and that these diets are well managed by the inclusion of a clinical dietitian in the research team.
The evidence presented in this review suggests that probiotics containing L reuteri appear to be an effective treatment option for colic in breast-fed infants younger than 6 months. All of the studies selected for this review testing the effectiveness of probiotics were assessed as low risk for bias against the Cochrane Risk Bias Assessment Tool (40) and were considered high quality investigations. Although meta-analysis presented evidence for the effectiveness of preparations containing fennel, this evidence must be viewed with caution because the included studies were of variable quality, had methodological issues, and were assessed as medium or high risk of bias. There was limited evidence for the use of glucose, sucrose, lactase, and simethicone as effective treatments for infant colic in breast-fed infants. The studies presented herein were not without methodological issues and were of variable quality. The high level of heterogeneity between the studies examined is a limiting factor to this analysis. There is limited evidence for the efficacy of maternal dietary manipulation through randomised controlled trials, and more well-designed studies are required in this area.
Thomas Phaer on Good Breast Milk
Thomas Phaer (1510–1560), called by some the “Father of English Pediatrics,” in 1546 published, in English, a text entitled The Regiment of Lyfe in which he described the nature of wholesome breast milk and how to increase the yield of it. The passage is reproduced below exactly as written followed by a more liberal rendition with modern spellings.
The mylke is good that is whyte and sweete and when y droppe it on your nayle and do move your finger neyther fleteth abrod at every stering nor will hange faste upon your naile when ye turne it downe-ward, but the whyche is between bothe is beste.1 Sometime it chaunceth that the milke waseth, so that ye nource can not have sufficient to susteine the child, for which I will declare remedies… appropriate to ye encreasying the mylke in the breste. Pasneppe rootes and fenelle roots sodden in broth of chickens and afterward eaten with a little fresche butter maketh encrease of mylke within the brestes. Another. The powder of earth wormes dryed and drunken in the broth of a neates tonge is a singular experiment for ye same intent.2
1. This is the original breast milk nail test described by Soranus of Ephesus (fl. 98–138) in Gynecologia.
2. Good breast milk is white and sweet and a drop placed on your nail will neither immediately roll off, nor cling excessively. Sometimes it happens that breast milk dries up and the nurse has insufficient milk to sustain the child, for which I offer remedies to increase the milk. Parsnip and fennel cooked in chicken broth and eaten with a little fresh butter increases milk in the breasts. Also, powdered desiccated earthworms cooked in cow (neates) tongue broth yields the same intent.
—Submitted by Angel Rafael Colón
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Keywords:© 2016 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
fussiness; herbal teas; infant colic; irritability; L reuteri; maternal diet; medication; probiotics; reflux; simethicone; sucrose