In the last few years, infant milk formulas with a combination of prebiotic oligosaccharides (short-chain galacto-oligosacchrides [scGOS] and long-chain fructo-oligosaccharides [lcFOS]) have become commercially available. There are little data available related to the influence of prebiotics on gastrointestinal motility in preterm infants. In a study in healthy preterm infants, Boehm et al (1) demonstrated that preterm infants fed with mother's milk had lower stool consistency and higher stool frequency than infants fed a preterm bovine milk formula. Supplementation of the same formula with a mixture of scGOS and lcFOS resulted in a reduction in stool consistency and an increase in stool frequency. More recently, Mihatsch et al (2) demonstrated a clinically relevant reduction in the gastrointestinal transit time in preterm infants fed a formula supplemented with these prebiotics.
Electrogastrographic (EGG) studies in newborns (3,4) have demonstrated the absence of normal slow waves at birth and a maturation process that may be or may be not modulated by enteral feeding. Normal gastric electrical activity is detectable from 34 weeks of gestational age, after which the pattern is similar to the pattern of full-term infants. Gastric emptying can be assessed by ultrasonography, a noninvasive technique particularly suitable for young patients (5).
In the present study, we hypothesized that giving a prebiotic mixture to preterm, formula-fed infants would improve gastric electrical activity and emptying.
PATIENTS AND METHODS
Twenty healthy preterm infants completed a double-blind, placebo-controlled, randomized study assigned to receive a prebiotic supplemented standard preterm formula (0.8 g/dL of a mixture from scGOS and lcFOS, ratio 9:1) or the same formula supplemented with the same quantity of maltodextrin as placebo (see Table 1 for clinical data). The preterm newborns were formula-fed because breast milk was not available and were exclusively bottle-fed with the same standard formula throughout the intervention period. The daily formula intake was approximately 30 mL/kg/day at baseline and 90 mL/kg/day at the end of the study. The examinations were performed on 3 to 5 days and 15 days after the intervention period. Newborns with respiratory distress, congenital malformation, inborn errors of metabolism, and proven sepsis or infection were not included. The study design was approved by the ethical committee of the University of Bari and written informed consent was obtained from the parents.
Anthropometric measurements (body weight, length, and head circumference) were performed before the start of the study and at all subsequent visits. Additionally, parents were asked to complete a 24-hour dietary report and a 24-hour tolerance report. Adverse events were recorded throughout the study as they occurred.
Assessment of Gastric Electrical Activity
Gastric electrical activity was measured before starting the intervention (time 0) and after a feeding period of 15 days. After overnight fasting, the EGG recordings were performed at least 30 minutes before and after meals using an EGG recorder (UPS 2020; Medical Management Systems, MMS, Enschede, the Netherlands). Five silver–silver chloride electrodes (Clear Trace, ConMed, Utica, NY) were placed on the cleaned abdominal surface and the ground electrode was placed to the left costal margin as reported by Chen et al (6). All of the recordings and analysis of the EGG parameters (dominant frequency and normal slow-wave percentage) were reported elsewhere (4). In addition to the running spectra analysis (7) available with the EGG equipment, Redtech GiPC software was used to perform further EGG data filtering and analysis and only the EGG traces with the best-quality signal were used for the further analysis in the time domain. The EGG traces were visually inspected in a blind manner to compute the presence of time lag between 2 EGG channels on the minute-by-minute samples of the EGG traces (30 minutes basal or postprandial recording time). The time lag had to be at least 3 seconds and was calculated between the 2 channels placed along the antral axis (channel 2–3 and channel 3–4). Propagation was calculated as the percentage of samples in which a propagation was detected with respect to the 30 samples.
Assessment of Gastric Emptying
Gastric emptying was recorded before starting the intervention (time 0) and after a feeding period of 15 days, on the same day of the EGG recordings. The ultrasound gastric emptying examinations were always performed by the same investigator using a real-time apparatus (Image Point HX; Hewlett Packard, Palo Alto, CA) equipped with a 3.5-MHz linear probe. The gastric emptying was expressed as half-emptying time, and this parameter was calculated as previously described (5).
To detect a difference in the mean gastric emptying time of about 20 minutes, α = 0.05, a minimum number of 20 children (10 per group) were required for a power of 0.8. The data were analyzed first using simple descriptive statistics of centrality and dispersion. All of the data were expressed as mean ± SD, and parametric or nonparametric statistical tests were performed for continuous or discrete clinical variables, respectively. Because of the lack of normal distribution and the small number of newborns enrolled, the differences in EGG and gastric emptying parameters were determined by Mann-Whitney rank sum test. All of the differences were considered significant at a 5% level. The software package used for the statistical analysis was STATA (STATA version 4.0 Statistical Software; StataCorp, College Station, TX).
The most relevant clinical data at the start of the study are shown in Table 1. No difference was seen in the daily increase of body weight and no adverse events were reported (Table 2). The daily increase of body weight was satisfactory, being an average of 35 g/day. No difference was seen in the time allowed to feed at the start and at the end of the study between the 2 groups.
At baseline, EGG and gastric emptying data were similar in the 2 groups. After the intervention period, EGG parameters showed no differences in newborns receiving formula feeding with or without the prebiotic both for preprandial (dominant frequency 3.2 ± 1.2 vs 2.9 ± 0.3 cpm, scGOS/lcFOS group and placebo group, respectively, Mann-Whitney test NS; normal slow waves 60.3 ± 1.7% vs 68.2 ± 5.9% scGOS/lcFOS group and placebo group, respectively, Mann-Whitney test NS) and postprandial data (dominant frequency 3.5 ± 0.2 vs 3.5 ± 1.6 cpm, scGOS/lcFOS group and placebo group, respectively, Mann-Whitney test NS; normal slow waves 57.8 ± 11.1% vs 51.0 ± 26.4% scGOS/lcFOS group and placebo group, respectively, Mann-Whitney test NS). However, the prebiotic group shows a higher percentage of propagation with respect to placebo group (Fig. 1). As regards gastric emptying time, the half-emptying time recorded after the intervention period was about 30% faster in the prebiotic group compared with the placebo group (Fig. 2). Comparing the change in gastric emptying time over time, only the prebiotic group showed a significant faster half-emptying time at day 15 than baseline (Fig. 2).
This pilot study demonstrates the potential beneficial effects of a prebiotic mixture on gastric motility as shown by the faster half-emptying time and the percentage of propagation in the EGG signal. None of the newborns displayed adverse growth or behavioral effects confirming the safety and tolerance of this prebiotic mixture in preterms (8). The mean growth rate in weight, length, and head circumference did not differ in the 2 groups as reported by others in term infants (9). Maltodextrin was used as placebo, which is perfectly tolerated by infants and has no prebiotic effect at all due to its fast absorption. In most starter formulas, lactose is the only carbohydrate. However, in many follow-on formulas, maltodextrin is also part of the carbohydrate fraction; therefore, we decided to use maltodextrin as placebo to ensure the same carbohydrate intake in both groups. The development of gastric slow waves and effects of feeding in preterm and full-term infants have been reported by Zhang et al (10). Our study confirms a normal EGG activity in older preterm newborns, when frequency and percentage of normal slow waves were considered. As reported by several authors (11,12), the presence of uncoupling, that is, the lack of propagation among different EGG channels, can be associated with a normal EGG or in some cases with tachygastria. The electrical uncoupling induces a collision between slow waves propagating from ectopic sites and the normal pacemaker site, disrupting peristalsis and delaying gastric emptying (13). The newborns receiving the GOS/FOS mixture had a higher percentage of propagation with respect to the placebo group. The percentage of propagation is an index of efficient electrical gastric activity that leads to an efficient peristalsis and can explain the absence of EGG improvement in previous work on probiotics in preterms (14). In our study, newborns fed with prebiotic showed a more efficient EGG activity and a faster gastric emptying time than placebo group, confirming the crucial role of the electrical coupling in the modulation of mechanical activity and coordination. A faster gastric emptying time than that in the placebo group was seen in a previous study on the effect of probiotics in preterm newborns (14). The action of prebiotic on upper gastrointestinal motility can be explained by several physiological pathways. The most important mechanism seems to be mediated by bacterial metabolites such as short-chain fatty acids (SCFAs). Colonic SCFAs modify upper motility via polypeptide YY by inducing relaxation of the proximal stomach and lower esophageal sphincter, reducing gastric emptying (15). Presently, no data are available concerning the role of SCFAs in preterm newborns, but the mechanism of probiotics on gastric emptying may be the same as in adults. A faster gastric emptying in preterm infants can lead to shorter duration for luminal nutrients remaining in the intestine, prevent the inflammation cascade, and reduce the development of necrotizing enterocolitis (16).
In conclusion, feeding preterm infants with a formula supplemented with prebiotics may stimulate gastric emptying and improve maturation of EGG activity. The beneficial effect of adding prebiotics to a premature infant formula would provide new regimens for the prevention of necrotizing enterocolitis.
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Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
Electrogastrography; Gastric emptying; Newborns; Prebiotic