Journal of the American College of Nutrition, Vol. 25, No. 1, 12-19 (2006)
Published by the American College of Nutrition
Growth, Tolerance and Biochemical Measures in Healthy Infants Fed a Partially Hydrolyzed Rice Protein-Based Formula: A Randomized, Blinded, Prospective Trial
John B. Lasekan, Ph.D.,
Winston W. K. Koo, M.B.B.S., F.A.C.N.,
Jocelyn Walters, M.S.,
Michael Neylan, M.S. and
Steven Luebbers, M.S.
Ross Products Division, Abbott Laboratories, Columbus, Ohio (J.B.L., M.N., S.L.)
Department of Pediatrics, University of Tennessee, Memphis, Tennessee (W.W.K.K., J.W.)
Address correspondence to: Dr. Winston Koo, Hutzel Hospital, Department of Pediatrics, 3980 John R, Detroit MI 48201. E-mail: wkoo{at}wayne.edu
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ABSTRACT
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Objective: To evaluate growth, tolerance and plasma biochemistries in infants fed an experimental rice protein-based infant formula.
Design: Randomized, blinded, 16 week parallel feeding trial of 65 healthy infants fed either an experimental partially hydrolyzed rice protein-based infant formula fortified with lysine and threonine (RPF, n = 32), or a standard intact cow’s milk protein-based formula (CMF, n = 33) as a control. Assessments occurred at enrollment (average 2 days), 2, 4, 8, and 16 weeks of age.
Results: Growth as indicated by weight, length, and head circumference was not different between the 2 formula groups. All plasma biochemistries for both groups were within reference normal range. However, RPF group had lower phosphorus and urea nitrogen, lower essential amino acids except threonine, which was higher, and lower ratio of essential (including semi-essential) to non-essential amino acids. Differences in the concentrations and ratios of amino acids became less as feeding progressed with age. Plasma total protein, albumin, prealbumin, calcium, magnesium, and alkaline phosphatase were not different between groups.
Conclusion: Healthy infants fed an experimental partially hydrolyzed rice protein-based formula had normal growth, tolerance, and plasma biochemistry comparable to those of infants fed a standard intact milk protein-based formula, despite some differences in amino acid profiles.
Abbreviations: RPF = rice protein-based formula • CMF = cow’smilk protein-based formula
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INTRODUCTION
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Most infants are fed human milk or a cow’s milk protein-based infant formula during the first year. Infants who become intolerant to human milk or a cow’s milk protein-based formula are often switched to either a soy protein-based formula, protein hydrolysate formula, or free amino acid-based formula. However, some infants who are allergic to cow’s milk protein are also allergic to soy protein [1, 2]. Rice is one of the first cereals introduced to infants in many parts of the world and is well tolerated. Consequently, it is often considered to be hypoallergenic and is used in many elimination diets as the basis for diagnosis of food allergy [3]. Thus, a rice protein-based infant formula offers the potential as an alternative feeding for infants who do not tolerate standard formulas.
Preliminary reports have shown that an experimental rice protein-based formula is well tolerated in infants recovering from malnutrition and supported weight increase and nitrogen balance over a 2 to 8 week period comparable to a casein protein-based formula [4]. In infants with cow milk protein allergy, the use of rice hydrolysate formula during the second half of infancy was associated with normal growth and biochemical indices [5]. In children with multiple food-induced reactions and intolerance to cow milk or soy milk formulas, the use of rice protein-based formula was well tolerated in a masked, placebo controlled challenge test [6]. However, these feeding studies are of relatively short duration and data on its use in healthy young infants is lacking. Such data is critical to a comprehensive evaluation of its efficacy and safety as human milk substitute. This pilot study aims to test the growth efficacy, gastrointestinal tolerance, and plasma biochemical measurements of healthy infants receiving a partially hydrolyzed rice protein-based formula for the first 16 weeks after birth.
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MATERIALS AND METHODS
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Study Design and Subjects
This was a randomized, blinded, parallel study of infants fed either an experimental rice formula or standard commercial formula. Study subjects were healthy term infants whose mothers chose not to breastfeed. None of the infants are known to have congenital or acquired conditions that may interfere with feeding or growth. All infants had gestational age between 38 and 42 weeks with birth weights between the 5th and 95th percentiles on the intrauterine growth curves [7]. All infants had 5-minute Apgar scores >8 and were enrolled during the first week after birth. Infants were randomly assigned at enrollment to receive one of the two formulas until 16 weeks of age. The randomization schedule was stratified by gender and race. This study was approved by the Institutional Review Board for human subjects at the University of Tennessee-Memphis, and written informed consent was obtained from each subject’s parent.
Study Formulas and Feeding Procedures
The study formulas included an experimental partially hydrolyzed rice protein-based powdered formula (RPF) and a standard powdered cow’s milk intact casein protein-based formula (CMF). Both study formulas were produced by the same manufacturer, Ross Products, Abbott Laboratories, Columbus, OH. The RPF was based on a Neutrase enzyme (Novo Nordisk Biochem North America, Inc., Franklinton, NC) hydrolyzed rice protein concentrate (California Natural Products, Lathrop, CA) with a resultant 14% amino nitrogen as a proportion of total nitrogen. The CMF was a commercial casein-dominated (casein:whey = 82:18) Similac® with Iron. Study formulas were packaged in identical cans and provided 2828 kJ/L (20 kcal/fl oz) upon reconstitution. Specific written instructions on the reconstitution of study formula were provided to each parent. In addition, the written instructions were repeated verbally and parental understanding of these instructions was confirmed by the research personnel. All cans were labeled with coded identification to mask the identity of the study formulas. The nutrient levels in both formulas met the levels recommended by the Infant Formula Act of 1980 and subsequent amendments in 1986 [8], and the Life Sciences Research Office Expert Panel in 1998 [9]. Consistent with the recommended increase in protein concentration of infant formulas based on protein sources (such as soy and other vegetable proteins) with biological values less than that for casein [9], the RPF was formulated to be about 27% higher in protein than the CMF. The RPF also was supplemented with lysine and threonine, the two limiting amino acids in rice protein. Key nutrient and amino acid compositions of the formulas are provided in Table 1.
Parents were given sufficient amount of the assigned formula to feed their infants until the next study visit. Assigned study formulas were fed ad libitum throughout the study as the only source of milk. Parents were advised not to provide solids or other supplements including minerals or vitamins during the study period. Adherence to the feeding protocol was monitored by study personnel at each visit and by telephone between patient visits. Feeding tolerance and adverse events were monitored throughout the study.
Study Assessment
Infants were evaluated at enrollment and at 2, 4, 8, and 16 weeks. Parents completed written records of the volume of study formula taken by the infant and whether non-study formula was given to the infant, and indicators of gastrointestinal tolerance of study formulas including the occurrence of spit-up or vomit, and descriptions of the number, color, and consistency of their infant’s stools, for 3 full days immediately prior to the scheduled study visits at 2, 4, 8, and 16 weeks. The stool color and consistency were based on parental selection from the list of standardized objective criteria established in previous studies [10, 11].
Measurements of growth (weight, length, head circumference) were obtained at enrollment, 2, 4, 8 and 16 weeks of age. Infants were weighed in the nude to the nearest g using a digital electronic scale (Air Shields, Vickers, OH) that was calibrated with known standard weights. Length was measured in duplicate to the nearest 0.1 cm with the infant in a recumbent position using O’Leary LengthboardTM (Ellard Instruments Ltd, Seattle, WA). Head circumference was measured in duplicate as the maximum occipital frontal circumference to the nearest 0.1 cm using a disposable paper tape measure. All anthropometric measurements were performed by one of the two investigators (JW or WK) with the help of a trained assistant using techniques adapted from standardized procedures [12]. In our laboratory, duplicate anthropometric measurements show similar intra- and inter-operator precision as determined by the method of Gluer et al [13] and were consistently <1% [14].
Nonfasting blood samples were obtained at enrollment, 4, 8 and 16 weeks of age. Plasma samples were stored at –70°C until measurements for calcium and magnesium by the spectrophotometric method; for phosphorus, alkaline phosphatase, total protein, albumin and blood urea nitrogen by colorimetric methods [15]; and for prealbumin by radial immunodiffusion [16]. Amino acids were derivatized and then quantified using Beckman 6300 Amino Acid Analyzer (Beckman Instruments, Palo Alto, CA) [17]. Plasma tryptophan was quantified by a reverse phase high performance liquid chromatography method [18].
Statistical Analysis
The two feeding groups were compared for birth and study entry and exit information using t test for continuous variables, and Chi-square tests for categorical variables. Growth measurements for weight, length and head circumference were normalized to Z scores using the age and gender matched anthropometrics data from the National Center for Health Statistics [19]. Growth data comparing the two feeding regimens employed repeated measures analysis of variance (ANOVA) with gender and race included as between subject factors. Subject’s race was dichotomized as either African Americans or Non-African Americans. Intake data was based on the average of the 3 day record and normalized to the weight in kg on the day of study visit and was analyzed by ANOVA with gender and race as factors in the model. Mean rank stool consistency characteristics rated on a 5-point scale and other data on gastrointestinal tolerance were analyzed using the ANOVA of ranked data. For plasma biochemistries and amino acid data, multivariate ANOVA was used to determine whether there were differences between groups at baseline, and the serial data were analyzed using repeated measures ANOVA with any statistically significantly different variable at baseline as covariate.
The study was designed to have at least 30 subjects complete each arm of the study. Based on the growth measures of normal infants [20], this sample size was expected to be sufficient to detect approximately 3% difference in length and 7% difference in weight between groups at 4 months with an 
of 0.05 and a power of 0.80. Statistical analyses were performed using SPSS, version 11.5 and employed two-sided significance testing at a p-value of < 0.05.
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RESULTS
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Subject Disposition
Eighty infants were enrolled into this study and 65 successfully completed the study according to protocol, with 32 in the RPF group and 33 in the CMF group. Fifteen subjects did not complete the study according to protocol; 8 were in the RPF group and 7 were in the CMF group. One subject from each group did not complete the feeding study due to intolerance to the assigned study formula. The remaining early study exits were either due to withdrawal by parents or failure to return for follow-up visits. There were no significant differences between the two groups in study completion or dropout rates or the reasons for study dropout. Clinical characteristics were similar in the two study groups (Table 2).
Growth, Formula Intake and Gastrointestinal Tolerance
There were no significant differences between the two study groups in any growth measurements. There were also no significant interactions between formula type with race or gender in growth measures (Table 3).
Details of the intake and tolerance to study formulas are shown in Table 4. The volume of study formula consumed with the corresponding energy and protein intake varied with time within each study group. However, there was no significant difference between the two groups in the intake of formula volume or energy. There was a corresponding higher protein intake (p = 0.001) in the RPF group since the protein content of RPF was higher by design. There was a significant independent race effect (p = 0.02) on the volume of study formulas consumed. African American infants consumed a greater amount of study formula with an average of 210 versus 180 mL/kg for other infants. The racial effect also impacted energy and protein intake since these variables are directly related to the volume of formula fed. The frequency of spit-up or vomiting varied widely for both groups and was highest at 8 weeks. There were no significant differences between groups in the daily number of stools or stool consistency. The RPF group had fewer brown stools initially, but both groups had yellowish green stools as feeding progressed.
Plasma Biochemistries and Amino Acids
The omnibus F value (F < 1) showed no significant difference between groups in baseline biochemistry measurements. Within each group, most plasma biochemical measures showed minor variability during the study (Table 5) although all values remained within the normal reference ranges [21, 22]. There were no significant differences in biochemical measures between groups except for the lower overall blood urea nitrogen and phosphorus in the RPF group.
The omnibus F value (F < 1) showed no significant difference between groups in baseline amino acids measurements. Within each group, plasma concentrations of all amino acids except phenylalanine varied with age but remained in the normal reference range [22]. The RPF group had significantly lower concentrations for all essential amino acids except threonine and cystine. Plasma threonine was higher in RPF group and cystine was not significantly different between groups (Table 6). For plasma non-essential (dispensable) amino acids concentrations, the RPF group had higher arginine and glycine but lower asparagine and proline (data not shown). The ratio of total essential to total non-essential amino acids increased during the study in both groups and was significantly lower in the RPF group (Table 6). However, the magnitude of the differences in this ratio and in individual amino acids decreased as feeding progressed.
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Table 6. Plasma Essential and Semi-Essential Amino Acids (µmol/L), and Ratios of Essential (EAA) to Nonessential Amino Acids (NEAA)*
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DISCUSSION
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The low protein content (about 7.3%, dry weight basis) and the very low lysine and threonine content of rice have limited its use as a complete protein source in infant formulas. However, the availability of rice protein concentrates fortified with lysine and threonine allows the use of rice protein in infant formulas. Our study is the first report of successful exclusive use of an experimental infant formula based on partially hydrolyzed rice protein fortified with lysine and threonine in healthy infants during the first 4 months after birth. By design, the duration of this pilot study over the first 4 months after birth was to minimize any confounding effect from the introduction of solid foods and mixed feeding in older infants and is consistent with the recommendation that either breast milk or formula should be used as the exclusive source of nutrient for the infants during first 4 to 6 months [23].
We demonstrated that this experimental rice based formula was efficacious in promoting normal growth in healthy term infants over the first 4 months after birth, the primary objective of our study. The growth of study infants was no different than that of infants fed a standard commercial formula used as thecontrol in this study which has been shown to support normal growth and development comparable to human milk [24, 25]. The use of Z scores eliminated any potential bias from absolute growth measures due to gender specific differences in growth and minor differences in gestation or chronologic ages. Its use also allows the comparison against population norms for healthy infants born at term. In this study, the generally increasing Z scores of anthropometric measurements in both groups during the study provided added assurance that the growth data were comparable to the normal population. The successful use of this experimental rice formulation up to 4 months provides a foundation for future studies of its use throughout the first year. This would be critical to the comprehensive evaluation of its efficacy and safety as human milk substitute.
This normal growth resulted from comparable volume of study formula and energy intake although the RPF group had higher total protein intake as a consequence of the higher protein content of the rice-based formula. The impact of the differences in fat and carbohydrate sources between the two study formulas on growth was not evaluated in this study. The slightly higher intake of formula by African American infants is unlikely to be of significant clinical consequence as there was no direct or interaction effect from race on growth or any other variables analyzed.
Recent studies have successfully measured occurrence of spit-up/vomits, frequency of stools, mean rank stool consistency and stool color in infants and used them as indicators of gastrointestinal tolerance to infant formulas [10, 11]. In the current study, the tolerance and acceptability of this experimental rice protein-based formula were at least similar to those of the standard milk protein-based formula in normal infants and is consistent with other reports that rice protein based formula is well tolerated [4–6]. Infants fed the experimental rice formula tended to have a lower incidence of spit-up and vomit compared to infants fed milk-based formula and was similar to the trend towards a reduction in spit-up noted with the feeding of soy protein-based formulas [26, 27].
Our data’s demonstration that rice based formula is well tolerated in healthy infants is consistent with the findings of studies showing its tolerance in malnourished infants [4] and in infants and young children with multiple allergies [5, 6]. In addition, it does not have the unpleasant odor, taste and flavor commonly associated with extensively hydrolyzed milk-based formulas [28]. However, this pilot study was not designed to test the hypoallergenic potential of the rice protein-based formula and further extensive studies are needed to determine its role as an alternative milk-free formula feeding for infants with sensitivities to soy protein-, cow’s milk protein-, or partially hydrolyzed milk protein-based formulas.
The changes in plasma biochemistries in the study subjects mirrored those for the normal population and complemented the observed normal physical growth of infants fed the RPF and CMF. The incremental rises in albumin levels occurred to a similar extent in both groups. These changes also correspond with increase in growth measurements and would support the adequacy of dietary protein intake in both groups of infants [29]. The lower urea nitrogen in RPF group presumably reflects the bioavailability of the nitrogen source of this experimental rice-based infant formula for tissue protein synthesis and growth. There were no significant differences in serum calcium concentrations despite a significantly higher calcium fortification of RPF. This is consistent with the recommendation for higher calcium fortification of non-milk based infant formulas to compensate for lower calcium bioavailability due to phytate or other components [8, 9]. The difference in phosphorus concentrations may reflect the difference in its bioavailability between the two formulas. In any case, the phosphorus concentrations were within the reference range and the differences were small. When coupled with the finding of normal growth and no differences in alkaline phosphatase, it is unlikely to be of clinical significance.
Our data showed there were significant group and time interactions for multiple plasma amino acids. This is consistent with other reports that postprandial plasma amino acid profiles are usually reflective of the amino acid patterns of proteins consumed [24, 29]. The plasma levels of essential amino acids for both groups were comparable to the normal reference ranges for healthy infants although they were higher in the CMF group compared to RPF group. This also accounted for the higher essential to non-essential amino acids ratio in infants fed CMF. The levels of essential amino acids and the ratio of essential to non-essential amino acids were similarly found to be higher for infants fed either casein- or whey-predominant cow milk based formulation compared to those fed human milk [24, 29]. The higher level of plasma threonine noted with the RPF feeding in our current study was consistent with threonine supplementation.
In our study, the magnitude of the differences in amino acid profiles between infants fed RPF and CMF decreased as feeding progressed with age. Whether this reflects the convergence of the lower requirement for essential amino acids or less interference from postprandial state due to increased interval between feeds is not known. The use of fasting samples in young infants is impractical under clinical conditions since the optimal duration of fasting at each sampling age is not known, possible lack of parental cooperation and ethical concerns. However, the use of postprandial samples in this pilot study did not appear to diminish the validity of the amino acid values, and our findings are comparable to those of other investigators [24, 29] and normal ranges [22] for infants. It is also not known whether the difference in plasma profile persists when these formulas are consumed beyond the study period and whether this has any clinical implications. In any case, the plasma total protein, albumin and prealbumin concentrations were almost identical between both groups indicating no differences in protein status for these groups.
In conclusion, our pilot study data show that the experimental partially hydrolyzed rice protein-based formula fortified with lysine and threonine when used as the exclusive source of infant formula was adequate in supporting normal growth and biochemistries in healthy term infants during the first 4 months after birth. Differences in plasma amino acid profile between infants fed rice-based versus cow milk-based formulas exist although the magnitude of these differences decreased with progression of feeding and plasma protein status remained normal in both groups. Additionally, the experimental rice formula in infants was well tolerated and comparable to that of the standard formula.
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ACKNOWLEDGMENTS
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This study was funded in part by Ross Products Division, Abbott Laboratories, Columbus, OH, and The University of Tennessee—Memphis Clinical Research Center, USPHS grant RR 00211-29.
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FOOTNOTES
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Disclosure: J.L. and S.L. are current employees, and MN is a former employee of Ross Products Division, Abbott Laboratories, Columbus, OH.
Received August 24, 2005.
Accepted November 30, 2005.
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ABSTRACT
INTRODUCTION
