Hong Kong Journal of Paediatrics [HK J Paediatr (New Series) 2022;27:182-187]

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Introduction

Infantile colic was first described by Wessel et al¹ in 1954 as crying or restlessness lasting for three or more hours a day, three or more days a week, for three or more weeks in an otherwise healthy infant. These episodes are also called "first three months colic". This is seen in 5-25% of infants.^2,3 Excessive crying is a very common complaint in the first three months after birth. Infantile colic can be observed in 2-week-old infants at the earliest, and the restlessness and crying episodes usually peak at 6-8 weeks after birth, often regressing around the 3rd-4th month.^1,4-6 These episodes of crying, restlessness and excessive gas may begin and regress in the absence of any clear trigger or cause, making it difficult to prevent or treat infantile colic.^1,4-7 The aetiology of infantile colic is still uncertain, although some authors have proposed a number of theories. These include excessive gas production and intestinal contraction, hypersensitivity to cow's milk protein, temporary lactase deficiency, maternal depression, insufficient bond between mother-infant or excessive stimulation of parents, difficult temperament of the infant and insecure attachment of the parents.^5-9 Most importantly, research has shown gut microbiota to have a crucial role in the aetiology of infantile colic.^10-13 Infants with and without infantile colic are reported to have considerably varying gut flora.^11,13,14 Studies supporting this have shown infants with infantile colic to have insufficient lactobacilli and excessive Clostridium difficile, Escherichia spp., and Klebsiella spp. in their gut flora.^11,15 Probiotics are defined as "living microorganisms that provide health benefits to their host when in sufficient amounts".¹⁶

Our study was carried out with the aims of investigating the effectiveness of Lactobacillus reuteri DSM 17938 (L. reuteri) on complaints of crying episodes and restlessness commonly seen in infants with infantile colic.

Material and Method

Patients

This study was conducted between October 2017 and April 2018 on 38 infants aged from 1 to 4 months who were fed breast milk or baby formula. The Rome IV criteria⁴ were used for infantile colic diagnosis. Ethics committee approval was obtained from the local ethics committee before the study, along with written and oral consent forms from the families of the infants. Infants aged between 1-4 months diagnosed as infantile colic according to the criteria of Rome IV¹⁷ were included the study. Infants were excluded if they were diagnosed with otitis media, urinary tract infection, stomatitis, meningitis, peristalsis problems, gastroesophageal reflux, invagination, hernia, corneal abrasion, foreign body in the eye, hair tourniquet, child abuse, drugs that pass through breast milk, cow's milk allergy, vaccine reaction, drug withdrawal in newborns, west syndrome, delayed maturation in neurological maturation, arrhythmia (supraventricular tachycardia) and congestive heart failure. Patients and infants who had used any probiotics in the last month were also excluded.

Double-blinded Study Design, Randomisation and Treatment

Patients diagnosed with infantile colic in the pediatric gastroenterology outpatient clinic of our hospital were directed to a Pediatric Gastroenterology Nurse and given boxes with unknown contents and only a code number. Two separate treatments were administered as probiotic and placebo. The two treatments were given by drugs completely identical in terms of colour, odor, taste and packaging properties, but with differing code numbers on the package, which were unknown to the doctor, the nurse and the patient and only known to the manufacturer.

This study was carried out prospectively, with the first group receiving probiotics treatment and the second group receiving placebo treatment. The first group was given 10⁸ colony-forming units (CFU) of L. reuteri once a daily for 28 days regardless of the diet (breast milk or baby formula), while the second group was given a placebo completely identical in terms of colour, odor, taste and packaging properties. While the probiotic product is 5 ml and packaged to contain 5 drops of 10⁸ CFU L.reuteri, sunflower oil, medium chain triglyceride oil and silicon dioxide (Biogaia^® 1x10⁸CFU/5 drops), the placebo product has the same content without L.reuteri. Receiving treatment was terminated if symptoms like abdominal pain, distention or vomiting were developed which were not seen before the treatment.

Evaluation of Outcome Measures

The primary outcome measures are complete regression of complaints and improvement in daily crying times by more than 50% after the 28-day probiotic treatment. The secondary outcome measures are improvement in mean total daily crying episodes and restlessness times and improvement in frequency of probiotic side effects such as nausea and vomiting after the 28-day treatment.

Mean total crying and restlessness times after the 28-day treatment were compared between both groups, along with any improvement in daily crying episodes and restlessness times. Those with more than 50% regression in daily crying times were evaluated separately. In data collection, those containing the same code number were collected under the same group. The results were compared according to the code numbers. The data were analysed by a statistician blinded to the contents of each code number, and the statistical significance between the groups was examined. The contents of the codes were ultimately revealed, and the probiotic and placebo names corresponding to the codes were written in tables and figures. A chart was given to the relatives of the patients and they were recommended to mark the treatment they used daily. Patients with deficiencies in the schedule were considered as non-compliant with treatment.

Statistical Analysis

The SPSS 15.0 (SPSS Inc. Chicago, IL, USA) version package software and the Microsoft Office Excel 2010 version were used in statistical analyses. Data comparison was done using the Mann-Whitney U Test and the Chi-Squared Test. In descriptive statistical analysis, numerical variables are given as mean ± standard deviation, and categorical data are given as number and percentage. The level of significance was taken as p<0.05.

Results

In this study, 56 patients were diagnosed with infantile colic. Seven patients were excluded as they refused to participate. The remaining 49 patients consisted of two randomly selected groups with double-blind treatment (26 in the probiotic group and 23 in the placebo group). However, 6 patients in the probiotic group and 5 in the placebo group were excluded during follow-up as they did not complete the treatment. Therefore, the probiotic group consisted of 20 patients, while the placebo group consisted of 18. The flow chart of the patients is shown in Figure 1. There was no difference between the groups in terms of findings at admission, age or gender distribution (Table 1). The patients had a mean age of 3.23±0.24 months and a female/male ratio of 0.92. At the end of the 28-day treatment, mean total crying episode times were 945±420 minutes in the probiotics group and 1205±450 minutes in the placebo group, with a statistically significant difference (p=0.041). Similarly, after treatment, mean total restlessness times were 1005±390 minutes in the probiotics group and 1155±345 minutes in the placebo group, with a statistically significant difference (p=0.037). In addition, after treatment, daily crying episodes and restlessness times were decreased by 23 and 25 minutes in the probiotics group, respectively (p=0.017 and p=0.026, respectively). This difference was also statistically significant. In the placebo group, daily crying episodes and restlessness times were reduced down to 42 and 41 minutes after treatment, respectively, but the difference was not statistically significant (p=0.319 and p=0.273, respectively) (Table 2). The number of infants with a 50% decrease in mean crying time after the 28-day treatment was 12 in the probiotics group and 5 in the placebo group, with a significant difference (p=0.046) (Figure 2). No side effect has been observed in any of the patients during the study.

Table 1 Comparison of groups according to demographic characteristics and application symptoms

Parameters Placebo Probiotic p

n 18 20 0.745*

Age (month) 3.05±0.12 3.49±0.36 0.307*

Gender 10 Male 11 Male 0.714

8 Female 9 Female

Breast milk 12 13 0.418

Baby formula 6 7 0.561

Daily crying crises (time-min) 49 47 0.826

Daily restlessness (time-min) 46 45 0.724

*Mann Whitney U test was applied and Chi Square test was applied to others.

Table 2 Symptoms of infantile colic before and after 28 days of treatment, by study group. Values are numbers of patients with each complaint

Symptoms Placebo Probiotic

BT AT p¹* BT AT p¹*

Daily crying crises (time-min) 49 42 0.319 47 23 0.017

Daily restlessness (time-min) 46 41 0.273 45 25 0.026

AT AT p²*

Total crying crises (time-min) 1205±450 945±420 0.041

Total restlessness (time-min) 1155±345 1005±390 0.037

BT: Before treatment, AT: After treatment, *Chi-square test
p¹ Comparison of daily crying and restless periods of placebo and probiotic groups before and after treatment
p² Comparison of total crying and restlessness times of both groups after treatment

Figure 1 Patient flow chart.

Figure 2 Comparison of the groups according to the number of babies whose crying time decreased by more than 50%.

Discussion

One comparative placebo study with L. reuteri on infants with infantile colic found that total crying and restlessness times and daily crying times were significantly decreased in the probiotics group.¹⁸ Another study with L. reuteri on infants only fed with breast milk reported that the probiotics group showed significant improvement in daily crying episodes and maternal depression.¹⁹ Szajewska et al²⁰ conducted a comparative placebo study with L. reuteri on infants only fed with breast milk and fed more than 50% of their diet with breast milk and found that daily crying times and crying episodes showed quicker improvement in the probiotics group. As a result of meta-analysis of 6 randomised controlled studies, Xu et al²¹ L. reuteri possibly increased the effectiveness of treatment for infantile colic and decreased crying time at two to three weeks without causing adverse events.

Our results show similarity to those mentioned above. Our study showed both mean total daily crying times and restlessness times to be significantly improved in the probiotics group. The studies mentioned above^18-20 reported improvement rates of 5-38% in their placebo groups, consistent with our rate of 27%.

However, contrary to our study, there are also studies in the literature reporting insignificant findings. A comparative placebo study by Sung et al²² with L. reuteri on infants fed with breast milk or baby formula showed no significant improvement in crying and restlessness times in the probiotics group. Another comparative placebo study by Savino et al²³ with L. reuteri reported no significant improvement in crying times in the probiotics group, but they observed a significant number of infants that yielded more than 50% improvement in crying times, similar to our results. Again, similarly, they observed no side effects in any patient.

Fatheree et al²⁴ with L. reuteri reported no significant improvement in crying, fussing times in the probiotics group but however, they have shown that it is safe to use as a single daily dose.

With clinical significance of 0.05, and a power of 80% to detect an absolute difference of 24% we needed a sample size of 30 patients for placebo and 30 patients for probiotic group. But our probiotic and placebo groups consisted of 20 and 18 patients respectively. This is the limitation of the study.

In conclusion, our study showed that L. reuteri helped significantly reduce crying episodes and restlessness times in infants with infantile colic. We observed no side effects in any of our patients due to L. reuteri use. However, we recommend that further studies with larger patient groups are needed for a definite judgement on the efficacy and safety of the use of L. reuteri.

Declaration of Interest

None

References
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