PEDIATRICS Vol. 111 No. 5 May 2003, pp. 1017-1023
Reduced Bone Mineralization in Infants Fed Palm Olein-Containing Formula: A Randomized, Double-Blinded, Prospective Trial
* Department of Pediatrics, Hutzel Hospital, Wayne State University, Detroit, Michigan
Hotel Dieu–Grace Hospital, Windsor, Ontario, Canada
Medical and Regulatory Affairs Department, Ross Products Division, Abbott Laboratories, Columbus, Ohio
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Objective. Palm and palm olein (PO) oils are used in some infant formula fat blends to match the fatty acid profile of human milk, but their presence has been shown to lower calcium and fat absorption. We aimed to determine if the reported differences in calcium absorption could affect skeletal development by comparing bone mineral accretion in healthy term infants fed a milk-based formula with (PMF) or without PO.
Methods. Whole body bone mineralization was evaluated in healthy term infants fed 1 of 2 coded, commercially available, ready-to-feed infant formulas in a randomized, double-blind, parallel study. Subjects were fed either 1) PMF formula (Enfamil with iron; Mead Johnson Division of Bristol Myers, Evansville, IN; N = 63) containing PO/coconut/soy/high-oleic sunflower oils (45/20/20/15% oil); or 2) milk-based formula without PO (Similac with iron; Ross Products Division Abbott Laboratories, Columbus, OH; N = 65), containing high-oleic safflower/coconut/soy oils (40/30/30% oil) from enrollment by 2 weeks after birth until 6 months. Anthropometrics and formula intake were determined monthly; total body bone mineral content (BMC) and bone mineral density (BMD) were measured at baseline, 3, and 6 months of age using dual energy x-ray absorptiometry.
Results. Intent-to-treat analyses indicated no significant differences between feeding groups in weight, length, head circumference, or formula intake throughout the study. BMC and BMD were not different at baseline but repeated measures analyses show that infants fed PMF had significantly lower BMC and BMD at 3 and 6 months.
Conclusions. Healthy term infants fed a formula containing PO as the predominant oil in the fat blend had significantly lower BMC and BMD than those fed a formula without PO. The inclusion of PO in infant formula at levels needed to provide a fatty acid profile similar to that of human milk leads to lower bone mineralization.
Key Words: palm olein • infant • bone • milk formula
Abbreviations: BMC, bone mineral content • BMD, bone mineral density • DXA, dual-energy x-ray absorptiometry • EVS, evaluable subject • ITT, intent-to-treat • MF, milk-based formula containing no palm olein • PMF, milk-based formula containing palm olein as the predominant oil • PO, palm olein • BA, bone area • SEM, standard error of the mean
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INTRODUCTION |
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Human milk has long been considered the model for the design of infant formulas. Over much of the history of the development of infant formula, most improvements have paralleled the emergence of analytical techniques that allowed more accurate and precise determination of various nutrients and their levels in human milk. Consequently, attempts at matching the composition of human milk have focused primarily on the quantity of various nutrients. However, there is now evidence that the quality of nutrients used in infant formulas is critical to nutrient bioavailability with measurable physiologic consequences.1 One such example is the selection of vegetable oils based on their fatty acid profile to be used in the fat component of infant formula. Palm oil and its low melting fraction, palm olein (PO), are used in many infant formulas to match the high palmitic acid content (
20% by weight of total fatty acids) of human milk.2,3 However, studies have shown that infants fed formulas containing PO at levels needed to match the palmitic acid content of human milk have lower absorption of both fat and calcium than infants fed formulas without PO.4,5 An important physiologic consequence of a reduction in calcium bioavailability would be a negative effect on the skeleton. To date, this specific aspect of PO fortification has not been studied in a longitudinal clinical study using current instrumentation to measure the accretion of bone mineral content (BMC) during infancy. This study was designed to determine if PO as used in commercially available infant formulas would result in decreased bone mineralization compared with formula without PO. The null hypothesis was that BMC would not differ between infants fed a formula containing PO as the predominant oil and those fed a PO-free formula during the first 6 months after birth. |
METHODS |
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Study Design and Subjects
This was a controlled, randomized, double-blinded, parallel feeding study evaluating bone mineralization in 2 groups of healthy term infants fed 1 of 2 formulas during the first 6 months. All study personnel and subjects’ parents were unaware of study formula assignment. Infants enrolled into the study were healthy singletons <2 weeks after birth, with a gestational age between 37 and 42 weeks, and whose mothers have decided on formula feeding. Written informed consent was obtained from a parent of each subject. On enrollment, infants were randomly assigned to receive 1 of the 2 formulas until 6 months of age. The study biostatistician prepared the randomization schedule that was stratified by gender and race. Formula assignment for each subject was placed in a sealed envelope and an envelope was selected according to the stratified groups on enrollment. Subjects were recruited in Detroit, MI, and Windsor, Ontario, Canada. All study procedures were conducted at the Hutzel Hospital, Wayne State University, Detroit, MI. The study protocol was approved by the Institutional Review Board for Human Investigations at Wayne State University, Detroit, MI, and the Research Ethics Board at Hotel-Dieu Grace Hospital, Windsor, Ontario, Canada.
Study Formulas and Feeding Procedures
The 2 study formulas were cow milk-protein-based, 1 with PO as the predominant oil, PMF (Enfamil with iron; Mead Johnson Division of Bristol Myers, Evansville, IN) and the other without PO, MF (Similac with iron; Ross Products Division Abbott Laboratories, Columbus, OH). Both study formulas were ready-to-feed, provided 20 kcal/fl oz, and were packaged in 32-fl oz cans and relabeled with coded identification for the purpose of masking the identity of the study formulas. The 2 formulas met or exceeded the minimum levels of nutrients recommended by the American Academy of Pediatrics Committee on Nutrition,6 and the Infant Formula Act of 1980 and subsequent amendments in 1986. The nutrient compositions of the 2 study formulas were generally comparable except for the fat blend (Table 1). The PMF had a fat blend of 45% PO, 20% coconut, 20% soy, and 15% high-oleic sunflower oils. The MF formula had a fat blend of 40% high-oleic safflower, 30% coconut, and 30% soy oils. As a result, the palmitic acid levels in PMF and MF were 22.1% and 8.2%, respectively.
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Parents were given a 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, and exclusively for the first 3 months. Parents were requested not to give mineral or vitamin supplementation during the study with the exception of fluoride drops if prescribed by the physician. Compliance was confirmed at each study visit. Parents completed 3-day dietary record forms at 3 and 4 weeks then monthly between 2 and 6 months of age to record the volume and frequency of formula feedings to their infants. Intake of solid foods and medications was also recorded. Feeding tolerance and adverse events were monitored throughout the study.
Study Assessment
Weight, length, and head circumference were measured at baseline, 1, 3, and 6 months of age using standard methods.7,8 Infants were weighed in the nude to the nearest 5 g using an electronic scale (Seca, Toledo, OH) that was calibrated daily. Length was measured in duplicate to the nearest 0.1 cm with the infant in a recumbent position using O’Leary Lengthboards (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 (Ross Products Division, Columbus, OH).
Total body BMC, bone area (BA), and bone mineral density (BMD) were determined by dual-energy X-ray absorptiometry (DXA) at baseline, 3, and 6 months of age. Two DXA instruments from the same manufacturer (Hologic Inc, Waltham, MA) were used. Twenty percent of the subjects had scans performed using the QDR 2000 and remaining subjects had scans on the QDR 4500A. Scan acquisition techniques including the use of an infant platform for QDR 2000 followed manufacturer’s recommendations. Scan analysis used software v5.73p for the QDR 2000 and vKH6 for the QDR 4500A. Both softwares have been previously validated.9,10 Only scans with no significant movement artifacts11 were included in the data analysis. At our center, the long-term (>4 years) coefficient of variation for the determination of BMC, BA, and BMD using an anthropomorphic spine phantom was <0.43%, 0.35%, and 0.31%, respectively, for both instruments. Data collected on the QDR 2000 DXA were standardized to that of QDR 4500A using a conversion factor validated in our laboratory. Both the raw and the standardized data were statistically tested to confirm that there was no statistically significant effect because of the type of DXA instrument used.
Statistical Methods
The sample size determination for this study was based on previous studies12,13 of healthy infants. We estimated that a sample size of 50 infants per group on completion of the study protocol would be sufficient to detect a .5 standard deviation difference in group mean BMC, the primary outcome variable. All statistical tests were 2-tailed using 
= .05.
The primary analyses in this study were "intent-to-treat" (ITT). These analyses included all available data on all randomized infants. Analyses were also done on an evaluable subject (EVS), which included subjects who received the assigned study formula throughout the 6-month study period as required by the protocol. BMC, BMD, anthropometric measurements, and frequency and volume of formula intake were analyzed using repeated measures analysis. Birth weights of subjects were included as covariates for the corresponding anthropometric analyses along with gender and race. Subject’s race was dichotomized as either African Americans (72 infants) or non-African Americans (56 infants: 48 White, 5 Hispanic, 1 Asian, and 2 multiracial). Analyses of BMC and BMD data were performed with the subject’s race and weight on the day of DXA scan as covariates, and with and without baseline values as covariates. Length on the day of DXA scan was strongly colinear with weight (adjusted r2 = .93, P < .001). Both the raw and standardized bone data were analyzed to determine if there was a significant DXA instrument effect or a DXA instrument by feeding interactive effect in the model.
Separate comparisons were made at individual study visits if feeding by visit interactions were significant. When there was a significant interaction of feeding with study visit (or with subject’s gender or race), a step-down Bonferroni procedure14 was used to adjust levels for the number of tests performed. Reasons for study exit were analyzed using Cochran-Mantel-Haenszel tests controlling for dichotomized race categories. Unless otherwise indicated, all values are mean ± SEM. All analyses were done using SAS Version 8 (SAS Institute, Cary, NC).15
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RESULTS |
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Disposition of Study Subjects
Clinical details of the 128 infants randomized into this study are shown in Table 2. One hundred and three infants (80.5%) completed the 3-month study visit and 102 infants completed the study through 6 months (79.7%). Twenty-six infants (20.3%) discontinued the study postrandomization. There were no significant differences between the feeding groups with respect to gender, race, or early study termination. PMF and MF groups had 11 and 15 subjects, respectively, that exited the study early. There were no statistical differences between the 2 groups with respect to the reasons for early study exit, which included formula intolerance, consumption of nonstudy formula, parental dissatisfaction, and removal from the study by the investigator for protocol violation. The early exit of 2 subjects in each group was rated by the investigator as "possibly related" to intolerance of the assigned study formula.
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Formula Intake and Growth
There were no significant differences in the daily frequency of feeding between the 2 feeding groups for either the ITT or the EVS analyses. For the ITT groups, the average number of feedings per day ranged from 7.6 to 7.8 at 1 month, 6.6 to 7.2 at 3 months, and 5.8 to 6.3 at 6 months of age. There were also no differences between feeding groups for the average daily formula intake in either the ITT or the EVS analyses after adjustment for comparison at multiple time points (Table 3). No subject in this study received mineral or vitamin supplementation. Solid food supplementation was initiated at 3 months in 13% and 19% of subjects in PMF and MF groups, respectively. This increased to 83% and 88% of subjects in these respective groups by 6 months, but the intake of solid foods remains limited. In general, growth was similar in both study groups. There was no significant difference between study groups in weight, length, or head circumference over the course of this study for either the ITT (Table 3) or EVS populations (data not shown).
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Bone Mass Measurements
Of the 128 infants enrolled into the study, 97 subjects (48 in the PMF group) had all scans performed on the QDR 4500A, 28 subjects (14 in the PMF group) had all scans performed on the QDR 2000 instrument, and for 3 infants (1 in the PMF group), the same instrument was used for 2 of the 3 scans. Therefore, the bone data collected on QDR 2000 was standardized to the data collected on the QDR 4500A. Statistical testing of the raw and standardized bone data confirmed that neither the type of DXA instrument nor the interaction between the type of DXA instrument and study feeding were significant when included in the model. Results were generally the same whether the analyses were based on the raw data from each instrument or adjusted using the cross-calibration factor relating to these instruments, or with or without the 3 subjects whose scans were performed using both instruments.
In the ITT analysis, BMC was not different between the study groups at baseline. Repeated measures analysis of covariance controlling for BMC at baseline, race, and weight on the day of scan showed that the PMF group had significantly lower overall BMC than the MF group (P < .001), and individual time point analyses indicated BMC was significantly lower at 3 and 6 months of age (Table 4). The ITT results were similar with or without controlling for BMC values at baseline, and with or without controlling length on the day of scan as an additional covariate. The same findings were obtained for BMD (Table 4).
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The results in the EVS analysis were similar to those seen in the ITT analysis for BMC (Fig 1) and for BMD (Fig 2). In the EVS group, the gain in BMC over 6 months averaged 9.5% lower in the PMF group (120 ± 4.0 g) than in the MF group (132.6 ± 4.4 g); the gain in BMD over 6 months averaged 11.1% lower in the PMF group (0.056 ± 0.002 g/cm2) than in the MF group (0.063 ± 0.003 g/cm2).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Most infant formulas that contain PO as the predominant fat source have fatty acid profiles, including the level of palmitic acid, that are closer to that of human milk than formulas without palm oil or PO. However, there are significant differences in the positional distribution of individual fatty acids on the triacylglyceride molecules that cause differences in fat and calcium absorption. Approximately 70% of palmitic acid in human milk is at the sn-2 position,16 whereas most of the palmitic acid in palm oil and PO is at the sn-1 and sn-3 positions.17 In the digestion of human milk fat, pancreatic lipase specifically hydrolyzes the fatty acids in the sn-1 and sn-3 positions, leaving saturated fatty acids such as palmitic and stearic acids as 2-monoacylglycerides, which then form mixed micelles with bile salts and are well-absorbed.18,19 In contrast, palmitic acid is hydrolyzed from the sn-1 and sn-3 positions from the triacylglycerides in palm oil or PO to form free palmitic acid. These free fatty acids couple to calcium to form unabsorbable calcium-fatty acid-soap complexes, thereby contributing to low calcium and fat absorption,20,21 low weight gain,22 and increased stool hardness.20,21,23 The effect of PO or palm oil in decreasing fat or calcium absorption or both has been demonstrated in term infants,4,5,20,23 preterm infants,21,24 and in rats.25
The current study extends the clinical observation that the use of PO in infant formula decreases calcium absorption5 by demonstrating an additional physiologic consequence; specifically, bone mass as BMC is also significantly decreased compared with infants fed formula without PO. The difference in BMC between study groups at 6 months was 7.3%, which represents a difference in the average daily accretion of 34 mg of bone calcium over 6 months. This is equivalent to the need to ingest approximately an additional 200 mL/d of the PO containing formula, assuming a 32.3% retention,4 to achieve a bone mass gain comparable to infants fed formula without PO.
Other investigators have also reported the influence of PO on infant bone mass accretion.12,23 Specker et al12 randomized neonates to a PO containing formula (Good Start; Carnation Company, Glendale, CA) and a PO-free formula (Similac with iron), with a breastfed reference group. The breastfed group (when 28 of 31 infants were exclusively breastfed) had significantly higher BMC than those in the PO group at the onset of the study. However, the bone mass accretion of breastfed infants decreased with increasing consumption of PO containing formula (averaged 16 oz/d at 3 months and 23 oz/d at 6 months) and resembled that of infants who consumed the PO formula exclusively. By 6 months, both the "human milk" group and the group fed the PO formula exclusively were shown to have 11.5% lower total body BMC compared with infants fed formula without PO. The greater negative effect of PO formula on bone mass accretion as indicated by the larger BMC difference compared with the current study was presumably a combined effect of PO and lower calcium content (439 mg/L) of the formula. In our study, BMC remained significantly lower in infants fed the formula with PO, even with 20% greater calcium content (527 mg/L) relative to the earlier report.12 Thus, this gives further support for the concept of impaired calcium bioavailability from formula with PO leading to impaired bone mass accretion. The identical calcium content of both study formulas in the current study eliminates calcium level as a confounder in the interpretation of the bone mass data.
Our data are also consistent with another report23 in which the infants had an average of 4.8% lower total body BMC after 12 weeks of feeding with a control formula containing natural palm olein oil with 12% of palmitic acid in the sn-2 position versus those fed a formula containing synthetic triacylglyceride with 50% of palmitic acid at the sn-2 position. Both study formulas contained similar palmitic acid and calcium content. The control group also had a 4.4% lower BMC compared with a reference group of exclusively breastfed infants after adjustment for gender, current weight, length, and BA. The power of this report is uncertain as total body bone mass measurement was performed only on 1 occasion at 12 weeks in 30% of the subjects, and the statistical adjustment included multiple parameters that are strongly inter-related. In contrast, our study generated longitudinal data showing significantly lower BMC at 3 and 6 months of age in infants fed formula with PO. Nevertheless, the report by Kennedy et al23 provides clear evidence that the negative effect of PO on bone mass accretion was caused by the location of palmitic acid on the triacylglyceride structure, and not to the level of palmitic acid in the study formula.
For infants and growing children, it is now generally agreed that DXA determined BMC is the most appropriate index of bone mass accretion, as BMD is subject to variabilities associated with age, site, and techniques used in the measurement.26,27 We reported BMD data for the sake of completeness and the differences between study groups remained statistically significant with infants fed formula with PO having lower BMD compared with infants fed formula without PO.
In older children, a change in bone mass such as BMC is thought to be a result of altered bone length, bone width, or the extent of bone mineralization.28 In this study, there was no significant difference between groups in recumbent length and presumably bone length. DXA measurement in infants almost always required bundling of the infant during scanning, which precludes accurate measurement and therefore the extent of changes in bone width or in total body BA. Uncertainty of total body BA measurement also precluded the determination of the extent of changes in bone mineralization as indicated by changes in BMC per unit change in BA.28
It is well-known that bone mass is strongly predictive of bone strength in adults and mature animals,29,30 and we have demonstrated that the same relationship exist in growing animals.31 Therefore, the lower BMC in infants fed PO-containing formula may be associated with lower bone strength.
Whether the differences in BMC between infants fed formulas with or without PO would persist beyond 6 months is not known since there is no study of total body bone mass accretion of infants fed the same milk formula throughout the first year. However, epidemiologic studies have reported that early dietary intake may have long-term effects on bone mass,32,33 and since human milk or infant formula remains the dominant source of calcium throughout infancy, it is conceivable that the lower rate of bone mass accretion would persist as long as the same formula is being fed. In any case, infancy undoubtedly is the single 1-year period with the greatest proportion of bone mass accretion with over 300% increase in total body BMC,13 and with respect to the absolute amount of BMC gained, it is even comparable to any 1-year period during the rapid bone accretion phase of adolescence. We have previously demonstrated that fetal BMC can be raised by an average of 14% by improving calcium nutriture of mothers with poor dietary calcium intake.34 Thus, when coupled with the data from other investigators,12,23 the magnitude of positive influence on bone mass accretion in infants and fetus is far greater than the maximum gain in total body BMC of 2% over a 3-year period of pharmacological intervention in the elderly.35 The practical implication is that the goal of osteoporosis prevention through optimizing bone growth and thus peak bone mass29 can begin during fetal life and infancy.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Taken together, the current study and other studies12,23 indicate that merely matching the fatty acid profile of human milk with the use of PO in infant formulas may result in an unintended depression of bone mass accretion and may potentially be detrimental to optimal bone health. This is consistent with the European Society of Pediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition position statement that "although the composition of human milk can be a guide to that of infant formulas and breast milk substitutes, gross compositional similarity is not, in itself, an ideal determinant or indicator of the safety and nutritional adequacy of dietary products for infants."36
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ACKNOWLEDGMENTS |
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This work was supported in part by Ross Products Division, Abbott Laboratories, Columbus, Ohio.
We thank Marc Masor, PhD, Joan Jacobs, MA, and Russell J. Merritt, MD, PhD, for their review and suggestions for this manuscript.
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FOOTNOTES |
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Received for publication May 30, 2002; Accepted Oct 11, 2002.
Reprint requests to (W.W.K.K.) Department of Pediatrics, Hutzel Hospital, Wayne State University, Detroit, MI 48201. E-mail: wkoo{at}wayne.edu
This work was presented as an abstract at the Pediatric Academic Societies’ Annual Meeting; April 30, 2001; Baltimore, MD.
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 OTHER ARTICLES NOTED (25 Apr 2003 to 18 Jul 2003) Evid. Based Nurs., October 1, 2003; 6(4): e1 - 12. [Full Text]
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