Milk
Protein
Quantity
and
Quality
in the
Term
Infant
I. Metabolic
Responses
and
Effects
on Growth
Anna-Liisa J#{228}rvenp#{228}#{228},MD, Niels C. R. R#{228}ih#{228},MD,
David K. Rassin, PhD, and Gerald E. Gaull, MD
From the Children s Hospital and Department of Obstetrics and Gynaecology,
University of Helsinki, Finland; and Department of Human Development and Nutrition, New York State Institute for Basic Research in Developmental Disabilities,
Staten Island
ABSTRACT. The growth and metabolic response of
healthy, term infants during the first 12 weeks of life to
feeding one of two formulas or human milk have been
measured. Two groups of infants were fed ad libitum a
1.5 gm/100 ml bovine protein formula made up of either
60% whey and 40% casein proteins or 18% whey and 82%
casein proteins. A third group of infants was breast-fed
ad libitum. No consistent significant differences were observed among the groups with respect to rate of gain in
weight, crown-rump length, crown-heel length, or head
circumference. Blood urea concentration was significantly
higher, and there was evidence suggesting compensation
for an increased acid load from the second to the fourth
weeks in both of the formula-fed groups compared with
the breast-fed group. Blood cholesterol was significantly
lower in both the formula-fed groups compared with the
breast-fed group (P < .001) and lower in the group fed
the casein-predominant formula than it was in those fed
the whey-predominant formula (P < .05). Pediatrics
70:214-220, 1982; formula, human milk, proteins, term
infant.
Immunologic, anti-infective, endocrinologic, and
emotional advantages to breast-feeding the term infant have been descnibed.’5 The nutritional ad-vantages of human milk are less clearly
under-stood. Current recommendations, both in the
United States and in Europe, emphasize
breast-feeding as the regimen of choice for the healthy, term infant.7’8 Furthermore, it is urged that the constituents of formulas reflect the composition of human milk.78 Recommendations for the protein composition of such substitutes include ranges of 1.7 to 4.5 gm/100 kcal7 and 1.2 to 1.9 gm/100 nil.
Our previous investigations’2 in preterm infants showed that both the quantity and the quality of protein in the diet influenced the metabolic status of the infant. Preterm infants fed 3.0 gm/100 ml of casein-predominant formulas were subject to azo-temia, prolonged metabolic acidosis, hyperammo-nemia,9 and striking increases in concentration of amino acids in plasma and unine.’#{176}’2 These meta-bolic changes were much less striking in infants fed whey-predominant formulas, particularly in those infants fed 1.5 gm/100 ml rather than 3.0 gm/100 ml of protein. Many of these changes may reflect
the biochemical immaturity of the preterm infant.1314 Similar systematic studies comparing growth and metabolic responses to human milk or specially prepared, synthetic formulas do not exist for term infants. The present study was designed to investigate the effects of formulas prepared from bovine milk (1.5 gm/100 ml with either a 60:40 or an 18:82 ratio of whey to casein proteins) and of human milk on the growth and metabolism of healthy term infants.
Received for publication May 8, 1981; accepted Aug 24, 1981. Reprint requests to (N.C.R.R) University of Lund, Department
of Pediatrics in Malmo, Malmo General Hospital, 5-214 01 Malmo, Sweden.
Dr. Rassin’s current address: Division of I)evelopmental
Nutri-tion and Metabolism, Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77550.
PEDIATRICS (ISSN 0031 4005). Copyright © 1982 by the American Academy of Pediatrics.
MATERIALS AND METHODS
Subjects
ap-ethics.
* Values are means ± SD; 1.5 (60:40) is bovine protein
formula (1.5 gm/100 ml) composed of 60% whey proteins and 40% caseins; 1.5 (18:82) is formula composed of 18% whey proteins and 82% caseins.
t
P < .05 when tested against human milk group.TABLE 2. Composition of Feeding Regimens
Human Milk* 1.5
(60:40)t
propriate for gestational age as determined by Fin-nish intrauterine growth charts.’ Gestational age
was estimated according to the mother’s last
men-strual period. In cases with uncertain dates, clinical
criteria’6 were used.
Assignment of infants to breast-feeding vs for-mula was not done at random because of the ethical imperative not to dissuade a woman from breast-feeding. The majority of Finnish women wish to breast-feed. Indeed, during a two-year period the infants available for formula feeding consisted of seven whose mothers were unable to breast-feed during the first few postpartum days, one infant whose mother was receiving medications that were felt to contraindicate breast-feeding, and 16 infants who were put up for adoption. The mothers in the
last group, it should be noted, were of a lower social
class, unmarried, and participated in prenatal care
less regularly. This bias in assignment may account for the lower initial birth weight of the formula-fed infants (Table 1). Two mothers from the group of 23 infants originally available for formula feeding later decided to breast-feed. Within the formula-feeding group, infants were assigned at random to the two formulas within the first two days after birth. The lower average birth weight ofthe 1.5 gm/ 100 ml group (60:40) may be a result of the prepon-derance of female infants in that group and the
preponderance of male infants in the 1.5 gm/100 ml
group (18:82). Of the 37 infants who originally made up the breast-feeding group, 15 were eliminated because the mother was unable or unwilling to continue to breast-feed exclusively.
The infants were first assessed on day 5, the day of discharge from hospital, and subsequently at ages 2, 4, 8, and 12 weeks. The measurements and sam-ples done after hospital discharge were performed in the outpatient clinic of the Children’s Hospital, University of Helsinki.
Informed consent was obtained from all mothers
before any infant was accepted into the study. The
study was approved by the hospital committee on
Feeding Regimens
All infants were fed ad libitum in the breast-fed and the formula-fed groups. Two formulas in pow-dered form were especially prepared for this study by Wyeth Laboratories, Mason, MI. The formulas varied only in the ratio of the bovine caseins to the electrodialyzed bovine whey used (Table 2). The formulas were made to volume with glass-distilled, sterilized water and contained 1.5 gm of protein per
100 ml with either 60 parts electrodialyzed whey proteins to 40 parts casein proteins or 18 parts electrodialyzed whey proteins and 82 parts casein
proteins. The formula contained 67 kcal/100 ml (20 kcal/oz) as is customary for term infants rather than the 78 kcal/100 ml (24 kcal/oz) used in our study of preterm infants.9 From 2 weeks of age, the infants were given a daily supplement of 1,500 IU of vitamin A and 1,000 IU of vitamin D.
Although the infants were fed ad libitum, intakes of more than 1,000 ml of formula per day were discouraged. The mothers reported the volumes of formula given during the last few days prior to each period of assessment. Thus, an estimate could be made of the mean volume of milk consumed per day. No differences in mean intake between male and female infants could be detected; therefore, mean intake was combined for all infants (Table 3). Intake per kilogram of body weight decreased dun-ing the period from 8 to 12 weeks of age. The mean intake of all formula-fed infants from 2 to 12 weeks was 178 mI/kg/day, providing approximately 2.7 gm/kg/day of protein. No attempt was made to estimate the intake of the breast-fed infants.
Growth Measurements
Weight was measured on a scale accurate to ±5
TABLE 1. Data of Infa nts Studied*
Infants Followed to
Age 12 Wk
Weigh t (gm)
Birth Age 2 Wk
(M/F)
Human milk 22 (9/13) 3,619 ± 396 3,660 ± 362
1.5 (60:40) 10 (3/7) 3,280 ± 419t 3,334 ± 442t
1.5 (18:82) 11 (9/2) 3,490 ± 485 3,444 ± 420
1.5
(18:82)t
True protein (gm/ 1.0 1.5 1.5
100 ml)
Whey:casein ratio Approx 70:30k 60:40 18:82
(%)
Lactose (%) 7.3 6.0 6.0
Fat (%) 3.7 4.0 4.0
Ash (%)
. . .
0.3 0.3Solids (%) 12.3 11.8 11.8
Calories (kcal/100 67 67 67
ml)
Protein/calories 1.5 2.2 2.2
(gm/100 kcal)
* Adapted from R#{228}ih#{228}et al.9
t
Composition of formulas is described in Table 1 foot-note. Vitamin, mineral, and protein composition of these formulas is essentially that of corresponding two formulas previously reported.9gm. Crown-heel and crown-rump lengths were measured on a board with rigid head and foot boards affixed at right angles and a built-in milli-meter ruler. The mean of three observations of each growth measurement was used. Head circumference was measured with a steel tape. All growth deter-minations were made by the same individual (A.L.J.).
Blood and Urine Analysis
Mothers were requested not to feed their infants for two to three hours prior to each follow-up visit, but no attempt was made to record the frequency of feeds. During each visit, samples of venous blood were drawn and untimed urine samples were col-lected. Urine samples were stored frozen within 30 minutes of collection. Acid-base status and BUN were measured by standard clinical laboratory tech-niques. Serum total protein and albumin were de-termined by the methods of Doumas.’7 Blood cho-lesterol’8 and triglycerides’9 were measured at the 12-week follow-up visit. Samples of plasma and urine for amino acid analysis were obtained at each visit and the results reported in the accompanying paper.2#{176}
Statistical Treatment
Data obtained from the groups of formula-fed
TABLE 3. Volume of Formula Intake
Week Intake
Mean ± SD Median Range
(ml/kg/day) (mi/day) (ml/day)
2 183 ± 30 (19)* 600 450-800
4 188 ± 21 (18) 725 550-875
8 180 ± 23 (21) 850 700-1,000
12 164 ± 18 (20) 900 800-1,000
* Values in parentheses indicate number of infants for
whom this information was available. Data from both formula-fed groups were combined.
infants were compared with one another and with those obtained from the breast-fed infants using Student’s t test. Because not all measurements for each infant could be obtained at every follow-up visit, there are discrepancies in some of the numbers of tests reported in some of the tables.
RESULTS
Clinical Observations
No obvious differences in the occurrence of med-ical problems were noted among the infants in the various feeding groups. Upper respiratory tract in-fections were present equally in all three groups. Two infants in the formula groups had gastroenter-itis and three had constipation or meteorism; these gastrointestinal problems were not observed in any of the breast-fed infants. Prolonged jaundice was observed in three of the breast-fed infants.
Growth
Rate of increase in weight was calculated from week 2 rather than from birth, inasmuch as week 2 appears to be the point at which weight begins clearly to increase. Little difference could be ascer-tamed between the birth weight and the weight at week 2 (Table 1). No consistent differences in rate of increase in weight, crown-rump length, or crown-heel length were noted among groups of infants on the three feeding regimens (Table 4). Rate of in-crease in head circumference was greater in the breast-fed infants than in the infants fed the whey-predominant formulas but not greater than in those fed the casein-predominant formula. This differ-ence may be a function of the disproportionate number of female infants assigned to that group.
Metabolic Measurements
BUN levels increased in both formula-fed groups during the first two weeks of life and were
signif-Measurement Human Milk 1.5 (60:40) 1.5 (18:82)
Crown-heel length
cm/wk 0.80 ± 0.26 0.77 ± 0.13 0.78 ± 0.07
mm/m/wk 15.9 ± 5.3 15.6 ± 2.7 15.6 ± 1.2
Crown-rump length
cm/wk 0.57 ± 0.18 0.51 ± 0.07t 0.56 ± 0.11
mm/m/wk 16.4 ± 5.3 15.0 ± 2.4 16.3 ± 3.4
Head circumference
cm/wk 0.49 ± 0.22 0.40 ± 0.08t 0.43 ± 0.05
mm/m/wk 14.0 ± 6.6 11.5 ± 2.7t 12.4 ± 1.7
Weight increase from 2-12 wk
gm/wk 209 ± 59 203 ± 44 226 ± 35
gm/kg/wk 58.6 ± 19.5 62.5 ± 16.9 65.8 ± 14.4
* Values are means ± SD. Composition of formulas is described in Table 1 footnote.
I.
P < .05 when tested against group fed human milk.E
TABLE 5. Acid Base Data for Weeks 1, 2, 4, 8, and 12* Human Milk 1.5 (60:40)
pH
1 7.39 ± 0.04 7.40 ± 0.04 7.38 ± 0.02
2 7.38 ± 0.05 7.38 ± 0.09 7.38 ± 0.03
4 7.39 ± 0.03 7.42 ± 0.04 7.40 ± 0.04
8 7.40 ± 0.04 7.40 ± 0.06 7.39 ± 0.03
12 7.40 ± 0.03 7.39 ± 0.05 7.39 ± 0.04
Pco2 (mm Hg)
1 33.9 ± 5.1 32.3 ± 4.0 33.9 ± 2.7
2 39.4 ± 6.1 36.2 ± 6.5 33.8 ± 4.lf
4 37.7 ± 4.0 32.9 ± 6.5t 35.1 ± 5.0
8 35.7 ± 4.6 33.8 ± 4.5 37.3 ± 7.4
12 35.4 ± 3.4 34.9 ± 4.7 36.5 ± 2.2
Bicarbonate (mEq/liter)
1 21.5 ± 2.0 21.3 ± 1.8 20.8 ± 1.1
2 22.9 ± 1.5 21.8 ± 2.7 20.6 ± 1.7t
4 22.8 ± 1.4 21.7 ± 2.2k 21.9 ± 1.4t
8 21.8 ± 1.3 21.6 ± 2.5 22.3 ± 2.9
12 22.3 ± 1.3 21.6 ± 1.9 22.3 ± 1.8
Base excess (mEq/liter)
1 -3.37 ± 2.53 -3.28 ± 2.42 -3.98 ± 1.37
2 -1.74 ± 1.94 -2.83 ± 3.67 -4.35 ± 2.17t
4 -1.63 ± 1.83 -2.75 ± 2.76 -2.55 ± 1.89
8 -2.68 ± 1.74 -3.12 ± 2.82 -2.04 ± 3.41
12 -2.30 ± 1.74 -2.99 ± 2.33 -2.22 ± 2.32
*Values are means ± SD. Composition of formulas is described in Table 1 footnote.
t P < .01 when tested against corresponding group fed human milk.
:1:
P < .05 when tested against corresponding group fed human milk.icantly higher than those of the breast-fed infants from the fourth through the 12th week (Figure). In contrast, there was a trend for the BUN concentra-tion in the breast-fed infants to decrease during the course of the study, from 7.6 mmoles/liter in the first week of life to 5.6 mmoles/liter at 12 weeks of age.
No differences among groups were observed in the blood pH (Table 5). The Pco2, base excess, and
plasma bicarbonate findings suggest, however, that
WEEKS
Figure. Effect of feeding regimen on mean BUN. Open circles indicate infants fed formulas (statistical
signifi-cance, P < .05) vs infants fed breast milk (HM); 1.5
(60:40) indicates infants fed 1.5 gm/100 ml of whey pro-tein-predominant formula; 1.5 (18:82) indicates infants fed 1.5 gm/100 ml ofcasein protein-predominant formula.
during the period from two to four weeks after birth, there may have been an attempt on the part of the formula-fed infants to compensate for a greater acid load than there was on the part of the breast-fed infants. All values, however, fall into the range considered as normal.
Serum protein and albumin concentrations were not different among the various feeding groups (Ta-ble 6). Serum albumin concentrations tended to increase in all groups during the course of the study.
Blood total cholesterol concentration was signif-icantly higher in the infants who were breast-fed than it was in either of the formula-fed groups at 12 weeks of age (Table 7). The mean blood total cho-lesterol concentration of the infants fed the casein-predominant formulas was significantly lower than that of the infants fed the whey-predominant for-mula (Table 7). No statistically significant differ-ences were observed among the groups in the blood triglyceride concentration.
DISCUSSION
There were no striking and consistent differences in growth rate ofhealthy term infants fed ad libitum either breast milk or whey-predominant and
casein-predominant formulas, each providing 1.5 gm/100
ml of bovine protein, at least as measured by crude, short-term anthropometric measurements. Some statistically significant differences in the metabolic response of these infants to the various feeding
regimens were identified. Infants fed formulas pro-viding 1.5 gm/100 ml of either whey- or casein-predominant bovine protein had higher concentra-tions of BUN. There also was evidence suggesting metabolic compensation for an increased acid load
during the second to fourth postnatal weeks. For-mula-fed infants also have lower blood concentra-tions of total cholesterol.
Previous investigations into the growth of term infants fed either various formulas or human milk also have not detected differences in the rate of growth among feeding 21 .22 Infants fed 5ev-eral formulas and human milk ad libitum did not differ in their rate of growth.2’ Infants fed casein-predominant formulas containing 1.8 gm/100 nil of protein grew at a rate similar to that of the infants
in the present study.22 Reanalysis of our growth
data with regard to sex does not identify any differ-ences related to sex.
The volume of milk consumed by suckling term infants is usually estimated by weighing infants
before and after breast-feeding,23 and the volumes
of formula intake in previous studies were compa-rable with those in our study. The data of Lonnerdal et al24 permit an estimate to be made of the mean
TABLE 6. Serum Total Protein and Albumin Concen-trations for Weeks 1, 2, 4, 8, and 12*
Human Milk 1.5 (60:40) 1.5 (18:82)
Serum total protein
(gm/liter)
1 55.8 ± 4.0 58.6 ± 3.8k 57.1 ± 3.2
2 56.6 ± 4.5 54.6 ± 5.0 56.9 ± 1.8
4 54.1 ± 3.2 55.1 ± 4.0 52.9 ± 2.8
8 56.4 ± 2.4 54.4 ± 3.2k 55.1 ± 4.2
12 58.3 ± 3.4 58.4 ± 4.0 57.9 ± 3.7
Serum albumin
(gm/liter)
1 35.4 ± 2.9 37.4 ± 2.7t 36.6 ± 3.1
2 36.6 ± 2.6 38.1 ± 3.2 37.9 ± 1.6 4 38.2 ± 2.4 39.3 ± 3.6 36.1 ± 1.8t
8 40.9 ± 2.4 39.6 ± 2.0 41.3 ± 2.9
12 40.8 ± 1.8 42.3 ± 2.5k 42.4 ± 3.4
* Values are means ± SD. Composition of formulas is
described in Table 1 footnote.
t
P < .01 when tested against corresponding group fedhuman milk.
t
P < .05 when tested against corresponding group fedhuman milk.
volume intake of human milk in suckling term infants in Scandinavia. Approximately 740 mI/day or 170 mI/kg/day of milk is consumed at the breast during the period from 2 weeks to 3 months of age. If the true protein concentration of milk from
moth-ers giving birth to term infants is assumed to be 1
gm/100 ml,9’25 then the intake of the breast-fed infants is approximately 1.7 gm of protein per kilo-gram per day. In contrast, the formula-fed infants consume approximately 180 mI/kg/day (Table 3) containing 1.5 gm/100 ml or approximately 2.7 gm of protein per kilogram per day. Thus, the formula-fed infant consumes approximately 50% more pro-tein than the breast-fed infant. One must question whether or not the higher protein provided by such formulas contributes anything to the growth of infants, unless it is needed to compensate for lim-iting amino acid(s). More sophisticated measure-ments of growth would be helpful in making this
judgment.
The metabolic differences among the breast-fed and formula-fed groups of term infants are not as striking as those observed earlier in preterm infants fed pooled human milk and synthetic formulas,9’2 yet there are significant differences in metabolic responses to the various feeding regimens. The in-creased BUN concentration observed in the for-mula-fed infants in the present study is a reflection of the larger protein intake. Similar relationships between BUN and milk protein concentration have been reported previously.2627 The greater protein load in the formula-fed infants may also be respon-sible for the data suggesting transient attempts at compensation for an increased acid load. Late met-abolic acidosis has been observed previously in a few infants fed amounts of protein similar to those in the present study.28 Presumably, the term infant is biochemically more mature’14 and, therefore, better able to metabolize the extra protein supplied in the formulas than is the preterm infant.
It has been suggested on the basis of studies in the rat that the amount of dietary cholesterol dur-ing the time of suckling may influence the concen-tration of serum cholesterol in adult life.29 The suggestion was made that a diet high in cholesterol during neonatal life may stimulate the development of enzyme systems required for cholesterol
catabo-TABLE 7. Blood Cholestero 1 and Triglycerides at 12 Weeks*
Human Milk 1.5 (60:40) 1.5 (18:82)
Cholesterol (mmoles/liter) 4.45 ± 0.56 3.09 ± 0.29t 2.73 ± O.55t
Triglycerides (mmoles/liter) 2.19 ± 0.87 1.74 ± 0.33 1.75 ± 0.97
* Values are means ± SD. Composition of formulas is described in Table 1 footnote.
t
P < .001 when tested against group fed human milk. Blood cholesterol for 1.5 (60:40)lism.29 This hypothesis has not been confirmed in man.#{176}Human milk contains more cholesterol than formulas in which cholesterol-poor vegetable oils
are substituted for bovine fats. The concentration
of cholesterol in human milk is 12.6 ± 4.8 mg/100
ml,6’8 that of bovine milk is about the same, and that of proprietary formulas made with vegetable oils is virtually nil (R. G. Jensen, personal
commu-nication). Thus, the cholesterol in bovine milk is
considerably reduced during preparation of syn-thetic formulas. We and other investigators#{176}32 have found that formula-fed infants have considerably lower serum cholesterol than do breast-fed infants.
It
is of potential interest that the cholesterol con-centration of the infants fed the casein-predominant formula is lower than that of the infants fed the whey-predominant formula. These data suggestthat the lower plasma total cholesterol concentra-tion is not just a function of lower cholesterol in-take, but that it may be a function of the protein quality. This finding is consonant with our recent observations in preterm infants that addition of free cholesterol to the formula to the level we found in
pooled human milk without a concomitant change
in fatty acids9 does not increase plasma total
cho-lesterol concentration in the infant. It agrees with recent work showing that dietary protein can affect plasma total cholesterol in rabbits.34 It is also pos-sible, in light of recent evidence, that serum total cholesterol is higher in female infants than it is in male infants and that the lower serum cholesterol in the casein-predominant formula (whey to casein, 18:82) group than in the whey-predominant formula (whey to casein, 60:40) group is a function of the preponderance of female infants in the latter group. However, analysis of the data taking sex into ac-count does not support this hypothesis. Clearly,
further work must be done to determine whether
this difference related to protein quality or to sex. In conclusion, it is apparent from the present data that term infants fed ad libitum with human milk or with one of two bovine milk protein for-mulas grow equally well as measured by gross an-thropometric measurements. The metabolic re-sponse of the infants indicates that differences do occur among the various feeding groups. These differences are not as great as those we observed in preterm infants fed similar types of formula prepa-rations.9’2 The term infant appears to be better developed biochemically to cope with the increased protein load provided in the formulas than is the preterm infant. The term infant also is better able than the preterm infant to cope with the different
quality of protein present in the two formula
prep-arations. Nonetheless, the metabolic differences among the feeding groups may have long-term
ef-fects that have not been detected as yet. These data provide additional biochemical evidence that for-mulas presently available may not be the nutni-tional equivalent of human milk.
ACKNOWLEDGMENTS
This investigation was supported by The Sigrid Juse-lius Foundation; The Foundation for Pediatric Research, Finland; Wyeth Laboratories; and the New York State Office of Mental Retardation and Developmental Disa-biities.
We acknowledge the cooperation of Dr M. Kunnas of the State Maternity Hospital, Helsinki, and all the moth-ers who allowed us to study their infants. We thank Drs John Silverio, Rudy Tomarelli, and Dan Shaw of Wyeth Laboratories for their interest in these studies and for the careful and special preparation of the formulas used.
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Child-hood Prevention ofAtherosclerosis and Hypertension. New York, Raven Press, 1980, p 121
ISAAC WATTS ON OBEDIENCE TO PARENTS, AS VIEWED IN THE
EIGHTEENTH CENTURY
Isaac Watts (1674-1748), a non-conformist English preacher, was famous in his own time for his textbooks on Logick and on the Principles of Geography
and Astronomy. Today he is best remembered for his hymns and certain
moralistic verses for children. A favorite verse known to many past generations of British and American children is the following’:
REFERENCE
Obedience to Parents Let children that would fear the Lord,
Hear what their teachers say;
With reverence meet their parent’s word,
And with delight obey.
Have you not heard what dreadful plagues Are threatened by the Lord,
To him that breaks his father’s law, Or mocks his mother’s word? What heavy guilt upon him lies!
How cursed is his name! The ravens shall pick out his eyes,
And eagles eat the same. But those who worship God, and give
Their parents honor due,
Here on this earth they long shall live, And live, hereafter too
Noted by T.E.C., Jr, MD
