- Email: [email protected]
Feeding effects on growth during infancy∗
FEEDING EFFECTS ON GROWTH DURING INFANCY MICHAEL S. KRAMER, MD, TONG GUO, PHD, ROBERT W. PLATT, PHD, IRINA VANILOVICH, MD, ZINAIDA SEVKOVSKAYA, MD, IRINA DZIKOVICH, MD, PHD, KIM F. MICHAELSEN, MD, DMSC, AND KATHRYN DEWEY, PHD, FOR THE PROMOTION OF BREASTFEEDING INTERVENTION TRIAL STUDY GROUP*
Objective
To examine the effects of formula, other milks, other liquids, cereals, and other solid foods on growth during
infancy.
Study design Observational cohort study nested within a large (n = 17,046), cluster-randomized trial. We compared growth [weight-for-age, length-for-age, and weight-for-length z scores (WAZ, LAZ, WLZ) and head circumference (HC)] during the intervals 1 to 3, 3 to 6, 6 to 9, and 9 to 12 months, using hierarchical multivariate regression to control for size at the beginning of each interval, maternal education, geographic region, and urban versus rural location. Results Mixed BF and formula/other milk were associated with significantly higher (versus breast milk only) LAZ at 1 to 3 months (+0.038 and +0.047, respectively). In the 3- to 6-month interval, mixed BF and formula/other milk led to significantly higher WAZ (+0.125 and +0.139) and LAZ (+0.081 and +0.075), whereas cereal intake was associated with large and highly significant reductions in both measures (20.293 and 20.240) and in HC (20.291 cm). Mixed BF and formula/other milk continued to have positive albeit smaller associations From the Departments of Pediatrics and with WAZ and LAZ in the 6- to 9-month and 9- to 12-month intervals. Conclusions
Our results confirm the growth-accelerating effects of formula and other milks (versus breast milk) on weight and length gain throughout infancy, with a dose-response gradient and largest associations observed at 3 to 6 months. (J Pediatr 2004;145:600-5)
revious studies have consistently reported higher weight and length gains in infants fed formula and/or other milks compared with infants following World Health Organization (WHO)/UNICEF recommendations for prolonged and exclusive breast-feeding.1-6 Downward trajectory is observed in z scores among breast-fed infants, beginning at 2 or 3 months and lasting until approximately 12 months, with considerable but not complete catch-up by 24 months of age. The WHO is currently developing a new international infant growth reference based on infants who follow their feeding recommendations.7,8 Despite the general consistency of the studies, many questions remain unanswered concerning the effects of specific aspects of infant feeding on growth during infancy and beyond. For example, no consistent differences in head circumference (HC) have been identified in breast-fed versus formula-fed infants. Moreover, the sample sizes have been too small to detect independent associations with intake of cereals and other solid foods and of water, juice, and other liquids. Considerable recent interest has also been generated by the suggestion of growth effects attributable to differences in protein content between breast milk and most infant formulas, on the one hand, and the even higher protein concentrations of whole cow’s milk and other milks, on the other. Some investigators have also hypothesized a causal link between protein intake in infancy and long-term risk of adiposity and obesity,9,10 but previous studies have had insufficient sample sizes and durations of follow-up of infants fed either formula or whole cow’s milk to adequately test
P
HC LAZ PROBIT BF
600
Head circumference Length-for-age z score Promotion of Breastfeeding Intervention Trial Breastfeeding
WAZ WLZ WHO
Weight-for-age z score Weight-for-length z score World Health Organization
of Epidemiology and Biostatistics, McGill University Faculty of Medicine, Montreal, Quebec, Canada; Belarussian Maternal and Child Health Research Institute; the Department of Human Nutrition, The Royal Veterinary and Agricultural University, Frederiksberg, Denmark; and the Program of International Nutrition, Department of Nutrition, University of California, Davis, California. *Other members of the Promotion of Breastfeeding Intervention Trial Study Group are Natalia Bogdanovich, MD, PhD, and Gyorgi Shishko, MD, DMSc, Belarussian Maternal and Child Health Research Institute; Stanley Shapiro, PhD, Jean-Paul Collet, MD, PhD, and Thierry Ducruet, MSc, Department of Epidemiology and Biostatistics, McGill University Faculty of Medicine; Beverley Chalmers, PhD, Centre for Research in Women’s Health, Sunnybrook and Women’s College Health Sciences Centre, University of Toronto; Ellen Hodnett, PhD, Faculty of Nursing, University of Toronto; and Irina Mezen, BA, Department of Foreign Relations, Belarussian Ministry of Health. Drs Kramer and Platt are recipients of career investigator awards from the Canadian Institutes of Health Research. Submitted for publication Jan 24, 2003; last revision received Jun 7, 2004; accepted Jun 28, 2004. No reprints available from authors. Please address correspondence to: Michael S. Kramer, MD, The Montreal Children’s Hospital, 2300 Tupper Street, Room T-115, Montreal, Quebec H3H 1P3 Canada. E-mail: michael.kramer@ mcgill.ca. 0022-3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2004.06.069
Table I. Distribution of feeding variables at onset of four age intervals* Feeding variable
1 mo
Milk Breast milk only Mixed breast-feeding Formula/other milk only Water None Any Juice/other liquids None Any Cereal None Any Other solids None Any
3 mo
6 mo
9 mo
13,780 (82.2) 1610 (9.6) 1365 (8.2)
8517 (51.1) 2336 (14.0) 5825 (34.9)
5375 (32.7) 1554 (9.4) 9536 (57.9)
3437 (21.4) 1269 (7.9) 11,387 (70.8)
11,666 (69.6) 5094 (30.4)
11,088 (66.4) 5597 (33.6)
11,209 (68.0) 5272 (32.0)
11,038 (68.2) 5138 (31.8)
14,203 (84.7) 2557 (15.3)
6577 (39.4) 10,108 (60.6)
1943 (11.8) 14,538 (88.2)
1078 (6.7) 15,098 (93.3)
16,758 (100) 2 (0)
16,480 (98.8) 205 (1.2)
3701 (22.5) 12,780 (77.5)
654 (4.0) 15,522 (95.9)
16,569 (98.9) 191 (1.1)
12,964 (77.7) 3721 (22.3)
2426 (14.7) 14,055 (85.3)
476 (2.9) 15,700 (97.1)
Data given as n (%). *Numbers of missing values were 286 to 291 at 1 month, 361 to 368 at 3 months, 565 to 581 at 6 months, and 870 to 953 at 9 months.
Table II. Growth outcomes* in the 1- to 3-month interval Feeding variable Mixed breast-feeding Formula/other milk only Water Juice/other liquids Other solids
WAZ
LAZ
WLZ
HC
20.001 (20.031 to 10.030) 10.038 (10.001 to 10.074) 20.056 (20.097 to 20.014) 20.014 (20.073 to 10.045) 20.010 (20.043 to 10.023) 10.047 (10.007 to 10.087) 20.069 (20.114 to 20.025) 20.064 (20.128 to 20.00003) 20.010 (20.040 to 10.020) 10.002 (20.035 to 10.039) 20.018 (20.060 to 10.023) 10.031 (20.028 to 10.091) 20.005 (20.037 to 10.028) 20.038 (20.077 to 10.002) 10.038 (20.006 to 10.083) 20.017 (20.081 to 10.047) 10.102 (20.003 to 10.208) 20.015 (20.141 to 10.112) 10.136 (20.007 to 10.278) 20.055 (20.259 to 10.148)
*Point estimate (95% CI); WAZ, LAZ, and WLZ are expressed on the z score scale (ie, number of SDs from the reference mean); HC is expressed in centimeters. Feeding variables refer to the beginning of the 1- to 3-month interval, ie, those recorded at 1 month, and all effects of mixed breast-feeding and formula/other milk are based on breast milk only as the reference. All results are adjusted for the anthropometric outcome (WAZ, LAZ, WLZ, or HC) at 1 month, maternal education, region, and urban versus rural location.
this hypothesis. Such a hypothesis is supported by two small feeding studies reporting effects of protein intake on weight gain during infancy.11,12 Finally, previous epidemiologic investigations have been limited by several important methodologic problems common in observational (association) studies of infant feeding and growth, including inadequate control for socioeconomic status, regression to the mean (smaller infants will tend to ‘‘catch up,’’ whereas larger infants will have a tendency to ‘‘catch down’’), and reverse causality (the feeding given is dependent on growth up to the time of the feeding decision, so that feeding can be a consequence of growth, as well as growth being a consequence of feeding).13 Because of these questions and issues, we carried out an observational cohort study nested within a large randomized trial in the Republic of Belarus, in which we attempt to overcome the methodologic problems discussed above. Although we previously reported the results of both Feeding Effects on Growth during Infancy
experimental (as randomized) and observational analyses of infant growth from this study,13,14 those analyses were restricted to associations between growth and the duration and exclusivity of breast-feeding. In the current study, we also examine the effects of formula and whole milks; water, juices, and other liquids; and cereals and other solids within specific intervals during the first year of life.
METHODS The study methods of the Promotion of Breastfeeding Intervention Trial (PROBIT) have been described in detail.13,15 Briefly, 31 maternity hospitals and one each of their affiliated polyclinics (ie, the outpatient clinics in which children are followed for routine health care) were randomly assigned to receive a breast-feeding promotion intervention modeled on the WHO/UNICEF Baby-Friendly Hospital Initiative (experimental group) or to continue the maternity 601
Table III. Growth outcomes* in the 3- to 6-month interval Feeding variable Mixed breast-feeding Formula/other milk only Water Juice/other liquids Cereal Other solids
WAZ
LAZ
WLZ
HC
10.125 (10.096 to 10.154) 10.081 (10.046 to 10.116) 10.054 (10.013 to 10.094) 10.069 (10.016 to 10.122) 10.139 (10.116 to 10.162) 10.075 (10.047 to 10.102) 10.072 (10.040 to 10.104) 10.044 (10.002 to 10.086) 10.013 10.005 20.293 20.022
(20.018 (20.024 (20.386 (20.054
to 10.044) to 10.034) to 20.199) to 10.010)
10.020 10.018 20.240 20.007
(20.019 (20.017 (20.353 (20.046
to 10.058) to 10.054) to 20.127) to 10.032)
20.007 20.016 20.053 20.006
(20.050 (20.056 (20.183 (20.050
to 10.036) to 10.024) to 10.077) to 10.039)
10.023 20.023 20.291 20.054
(20.037 (20.078 (20.463 (20.114
to 10.084) to 10.031) to 20.120) to 10.006)
*Point estimate (95% CI); WAZ, LAZ, and WLZ are expressed on the z score scale (ie, number of SDs from the reference mean); HC is expressed in centimeters. Feeding variables refer to the beginning of the 3- to 6-month interval, ie, those recorded at 3 months, and all effects of mixed breast-feeding and formula/other milk are based on breast milk only as the reference. All results are adjusted for the anthropometric outcome (WAZ, LAZ, WLZ, or HC) at 3 months, maternal education, region, and urban versus rural location.
Table IV. Growth outcomes* in the 6- to 9-month interval Feeding variable Mixed breast-feeding Formula/other milk only Water Juice/other liquids Cereal Other solids
WAZ
LAZ
WLZ
HC
10.032 (10.001 to 10.062) 20.004 (20.044 to 10.035) 10.034 (20.009 to 10.077) 10.024 (20.033 to 10.082) 10.069 (10.049 to 10.088) 10.039 (10.014 to 10.064) 10.058 (10.031 to 10.086) 10.016 (20.021 to 10.052) 10.024 10.013 10.000 20.001
(20.003 (20.019 (20.027 (20.031
to 10.051) to 10.045) to 10.027) to 10.029)
20.001 10.040 10.017 20.002
(20.035 (20.001 (20.017 (20.041
to 10.034) to 10.080) to 10.051) to 10.036)
10.011 20.021 20.007 10.018
(20.025 (20.065 (20.044 (20.024
to 10.046) to 10.024) to 10.030) to 10.060)
10.073 20.016 10.045 20.045
(10.020 (20.076 (20.006 (20.102
to 10.127) to 10.044) to 10.096) to 10.012)
*Point estimate (95% CI); WAZ, LAZ, and WLZ are expressed on the z score scale (ie, number of SDs from the reference mean); HC is expressed in centimeters. Feeding variables refer to the beginning of the 6- to 9-month interval, ie, those recorded at 6 months, and all effects of mixed breast-feeding and formula/other milk are based on breast milk only as the reference. All results are adjusted for the anthropometric outcome (WAZ, LAZ, WLZ, or HC) at 6 months, maternal education, region, and urban versus rural location.
hospital and polyclinic practices in effect at the time of random assignment (control group). A 32nd site was also originally included as part of the study but was excluded because of falsification of outcome data. As then recommended by the WHO, the experimental maternity hospitals and polyclinics encouraged and supported mothers to exclusively breast-feed for 4 to 6 months and to maintain partial breast-feeding to 12 months and beyond. No other specific feeding recommendations were included in the experimental or control interventions. Healthy breast-fed term newborn infants of $37 completed weeks’ gestational age and weighing $2500 g at birth were enrolled during their postpartum hospital stay. Information on infant feeding, illness, and growth was collected at polyclinic visits at 1, 2, 3, 6, 9, and 12 months. A total of 17,046 infants were randomly assigned from the 31 study sites, only 555 (3.3%) of whom were lost to follow-up by 12 months of age. Because differences in growth were not major hypotheses of PROBIT, which focused on reduction in risks of infection and of atopic eczema, no attempts were made to standardize measurements of weight, length, and HC. The outcomes analyzed are based on the Centers for Disease Control/WHO reference, using EpiInfo 2000, and 602
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included the weight-for-age z score (WAZ), length-for-age z score (LAZ), weight-for-length z score (WLZ), and HC. To isolate the effects of several infant feeding variables at specific periods during infancy, we carried out separate analyses within the intervals 1 to 3, 3 to 6, 6 to 9, and 9 to 12 months. Feeding variables were defined at the onset of each of these intervals to protect against reverse causality (ie, change in feeding within the interval in response to changes in weight, length, or HC). To explore effects of differing protein concentrations, milk intake was initially categorized as breast milk only (the reference group), mixed breast-feeding (breast milk plus formula or other milk), formula only, formula plus whole cow’s or other milk, and whole cow’s or other milk only. Except for weight-for-length at 9 to 12 months (see Results), we found no differences in effects of formula versus whole milk intake for any of the growth outcomes within any of the age intervals. The results presented below are therefore based on a trichotomous classification for milk intake: breast milk only, mixed breast-feeding, and formula or other milk only. We also tested more quantitative analytic models based on estimated intake volumes for breast milk, formula, and other milks, with breast milk volume estimates based on the ‘‘breastfeeding intensity ratio’’ of Piper and Parks16 and the breast The Journal of Pediatrics November 2004
Table V. Growth outcomes* in the 9- to 12-month interval Feeding variable Mixed breast-feeding Formula/other milk only Water Juice/other liquids Cereal Other solids
WAZ
LAZ
WLZ
HC
10.036 (10.003 to 10.068) 10.010 (20.032 to 10.052) 10.026 (20.019 to 10.071) 20.034 (20.102 to 10.034) 10.040 (10.021 to 10.060) 10.034 (10.008 to 10.059) 10.051 (10.024 to 10.079) 20.049 (20.090 to 20.008) 10.008 10.026 10.029 20.045
(20.018 (20.016 (20.027 (20.102
to to to to
10.033) 10.069) 10.084) 10.011)
20.011 20.023 10.002 20.082
(20.045 (20.079 (20.070 (20.156
to to to to
10.022) 10.032) 10.075) 20.008)
10.002 10.061 10.052 10.040
(20.032 (10.003 (20.024 (20.039
to to to to
10.037) 10.119) 10.129) 10.119)
10.051 10.063 10.000 20.100
(20.004 (20.027 (20.117 (20.219
to to to to
10.105) 10.153) 10.117) 10.020)
*Point estimate (95% CI); WAZ, LAZ, and WLZ are expressed on the z score scale (ie, number of SDs from the reference mean); HC is expressed in centimeters. Feeding variables refer to the beginning of the 9- to 12-month interval, ie, those recorded at 9 months, and all effects of mixed breast-feeding and formula/other milk are based on breast milk only as the reference. All results are adjusted for the anthropometric outcome (WAZ, LAZ, WLZ, or HC) at 9 months, maternal education, region, and urban versus rural location.
milk volumes at each age reported by Brown et al.17 The results were less consistent than those using the simpler classification; thus the results presented below are primarily based on the latter. Intake of water, juice or other liquids, cereals, and other solids were each dichotomized as any versus none, with none as the reference group. Cereals were not included in the models for 1 to 3 months, since only 2 infants were consuming cereals at 1 month. Data were analyzed using hierarchical linear mixed models (PROC MIXED in SAS). These models included two stratum-specific covariates: (1) western (Grodno or Brest) versus eastern (all other) regions and (2) urban versus rural location of the maternity hospital. Individual-level covariates included the anthropometric outcome at the onset of each age interval (to control for regression to the mean and reverse causality) and maternal education (4 categories). A randomeffects term was also included in the model for maternity hospital at birth, and the individual-level covariates were nested within hospital to account for intraclass correlation of outcomes among infants born at the same maternity hospital. Thus, for each of the intervals studied, the outcome (WAZ, LAZ, WLZHC) was assessed at the end of each interval (ie, at 3, 6, 9, or 12 months) while controlling for the same outcome at the onset of the interval (1, 3, 6, or 9 months) and all of the other stratum and individual-level covariates listed above. This analysis is equivalent to an analysis of increases in anthropometric outcomes (ie, growth velocity) between the beginning and end of each age interval.
RESULTS Table I summarizes the distribution of feeding variables at the onset of the 4 age intervals. These results show the progressive addition/substitution of formula and other milks to breast milk with advancing age, consumption of water by approximately one third of infants at all ages, marked increases in juice intake with age, and the rare consumption of cereals before 6 months and of other solid foods before 3 months. The results of the hierarchical regression analyses are shown in Tables II, III, IV, and V for the 1- to 3-month, 3- to Feeding Effects on Growth during Infancy
6-month, 6- to 9-month, and 9- to 12-month intervals, respectively. In the 1- to 3-month interval (Table II), the main statistically significant effects were observed for LAZ and WLZ, with evidence of a dose-response relation of small magnitude between feeding of milks other than breast milk and higher LAZ and lower WLZ at 3 months of age. The largest effects of the study feeding variables on growth were observed in the 3- to 6-month interval (Table III). Nonbreast milk (formula and/or other milks) was associated with substantial increases in WAZ and smaller increases in LAZ, WLZ, and HC at 6 months. The most striking findings, however, were the large negative associations between cereal intake and WAZ, LAZ, and HC. No significant interactions were observed between cereal intake and breast milk only, mixed breast-feeding, and formula/other milk only (data not shown); in other words, the negative association between cereal intake and growth at 3 to 6 months was of similar magnitude in each of the 3 milk feeding groups. Our more quantitative estimates of milk intake (see Methods) suggested displacement by cereals; the proportion of infants consuming <500 mL of any milk (sum of breast milk, formula, and other milks) at 3 months was 9.3% versus 0.1% in those consuming versus those not consuming cereals at 3 months. Smaller but statistically significant associations between greater weight and length gains and formula/other milk feedings were also observed in the 6- to 9-month and 9- to 12month intervals (Tables IV and V, respectively). Unlike all other growth outcomes at all age intervals studied, we observed larger effects of other milks (versus formula) on WLZ at 9 to 12 months. Mixed breast-feeding was associated with an increase (versus breast milk only) in WLZ of 10.027 (95% CI, 20.018 to 10.071); the corresponding increases were 10.045 (10.016 to 10.074) for formula only, 10.059 (10.016 to 10.101) for formula plus other milk, and 10.064 (10.028 to 10.101) for other milk only. Intake of juices and other liquids was also associated with a significant increase in WLZ at 9 to 12 months. A statistically significantly larger increase in HC between 6 and 9 months was observed among infants who received water feedings at 6 months (Table IV). The increase 603
in head circumference between 9 and 12 months was statistically significantly smaller among infants who received only formula or other milk as the sole source of milk feedings at 9 months (Table V).
DISCUSSION Our results confirm the large and increasing body of evidence indicating that formula and other milks accelerate both weight gain and length gain during infancy, particularly after 3 months of age.1-6 Our large sample size enabled us to demonstrate a dose-response relation between non-breast milk or formula intake and both length and weight gain and to identify the 3- to 6-month interval as the time period in which these effects are largest. We also observed strong negative associations between cereal intake and length, weight, and HC gains in the 3- to 6-month interval. Previous studies have documented a reduction in breast milk intake in infants offered cereals and other solid foods during this critical time period.17,18 Our results confirm these negative effects and extend them to infants receiving formula and other milks as well. The energy, protein, and micronutrient content of most cereals are inferior to those of breast milk, formula, and other milks, and our results suggesting displacement of milk feeding by cereals during the 3- to 6-month interval may explain the observed adverse effect on growth. Another potential explanation for the strong negative associations with cereal intake is the high phytate content of many cereals, which can reduce zinc absorption and thereby limit growth during this age period.17 The negative associations we observed between receipt of cereals and growth between 3 and 6 months, however, are based on a very small proportion of infants who received cereals at 3 months (1.2%, see Table I) and should therefore be interpreted cautiously. Moreover, we have no information on the reasons for giving cereals, and thus the association we observed between cereal intake and low total milk volumes at 3 months could be explained by mothers’ attempts to compensate for low milk intakes by giving cereals rather than an adverse effect of cereal consumption on milk intake. Finally, the cereals given to infants in Belarus at the time of this trial were those traditionally consumed by adults, not the micronutrient-fortified, finely powdered product used in most Western countries. Thus, the effects of cereals we observed may not be generalizable to other settings. Some epidemiologic studies have suggested that prolonged and exclusive breast-feeding is associated with a reduced long-term risk of obesity,19-21 suggesting that these early differences in growth might ‘‘program’’ appetite, adipocyte proliferation, or energy metabolism. Longer-term follow-up of our PROBIT cohort will be required to assess whether the effects of formula and other milk on weight and length growth during infancy will persist and whether they are associated with obesity or other health outcomes later in childhood and adulthood. Although our sample size was large, we found no consistent differences in growth among infants receiving whole cow’s milk versus formula, despite the much higher 604
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concentration of protein in whole cow’s milk (approximately 4 g/100 mL) than in formula. Most formulas in the Republic of Belarus contain between 1.6 and 1.7 g/100 mL of protein, and thus our findings do not provide strong support for the hypothesis that protein intake is a major determinant of growth and adiposity, at least during infancy.9,10 We did, however, observe differences in WLZ at 9 to 12 months consistent with a dose-response effect of protein intake. The absence of such differences at other ages and for other growth outcomes suggests that these findings may have arisen by chance, although the lower protein requirements (in g/kg per day) at this age provides one potential mechanism for a true biological effect of higher protein intake on adiposity.22 We found no consistent effects of formula and other milks, cereals, or other solids or liquids on head growth. Slight increases in HC in infants who received formula or other milks between 3 and 6 months appeared to be counterbalanced by negative effects of similar magnitude between 9 and 12 months. Longer-term follow-up will be required to determine whether prolonged and exclusive breast-feeding has longerterm effects on head growth and whether those effects are associated with previously reported advances in neurocognitive development among such infants.23,24 Although we found an increase in HC at 9 months among infants receiving water feedings at 9 months, the small magnitude of the effect (0.073 cm) and the absence of effects of water on other measures or at other ages suggest that this finding is likely to have occurred by chance. Several limitations of our study require emphasis. This remains an observational (cohort) analysis and therefore does not benefit from PROBIT’s randomized trial design. Despite our best attempts to control for individual- and regional-level confounding variables, regression to the mean, and reverse causality, residual confounding (eg, caused by unmeasured differences in parental body mass index) and selection bias cannot be excluded in such an observational analysis. None of the specific feeding variables studied here (formula/other milk, water, juice, or other liquids, cereals, or other solids) were part of the randomized intervention, which promoted exclusive and prolonged breast-feeding, as advocated by WHO and UNICEF. Thus, an intention-to-treat analysis based on randomization cannot shed light on these nonrandomized feeding choices. Second, as mentioned in Methods, the primary outcomes in PROBIT related to infection and atopic eczema, not infant growth. Anthropometric measurements were carried out by 31 different pediatricians, with no attempt to standardize measuring instruments or measurement methods. The absence of such standardization, however, should increase random (nondifferential) error and therefore attenuate associations with infant feeding and other potential determinants. Finally, the long-term consequences of the effects we have observed remain uncertain. In particular, it will be important to determine whether these effects persist in terms of risk of obesity, age at puberty, and adult stature; whether they are associated with differences in neurocognitive development; and whether they are associated with risk factors The Journal of Pediatrics November 2004
for chronic adult diseases such as type 2 diabetes, hypertension, and coronary heart disease. Some of these consequences are currently under investigation as we follow up PROBIT children at the age of 6.5 years.
REFERENCES 1. WHO Working Group on Infant Growth. An evaluation of infant growth. Geneva: World Health Organization; 1994. 2. Dewey K, Peerson J, Brown K, Krebs N, Michaelsen K, Persson L, et al. Growth of breast-fed infants deviates from current reference data: a pooled analysis of US, Canadian, and European data sets. Pediatrics 1995;96: 495-503. 3. Dewey KG. Growth characteristics of breast-fed compared to formula-fed infants. Biol Neonate 1998;74:94-105. 4. Nielsen G, Thomsen B, Michaelsen K. Influence of breastfeeding and complementary food on growth between 5 and 10 months. Acta Paediatr 1998;87:911-7. 5. Hediger M, Overpeck M, Ruan W, Troendle J. Early infant feeding and growth status of US-born infants and children aged 4-71 mo: analyses from the third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr 2000;72:159-67. 6. Haschke F, van’t Hof M, Euro-growth study groups . Euro-Growth references for breast-fed boys and girls: influence of breast-feeding and solids on growth until 36 months of age. J Pediatr Gastroenterol Nutr 2000;31: S60-71. 7. de Onis M, Garza C, Habicht J. Time for a new growth reference. Pediatrics 1997;100:E8. 8. WHO Working Group on the Growth Reference Protocol and WHO Task Force on Methods for the Natural Regulation of Fertility. Growth patterns of breastfed infants in seven countries. Acta Paediatr 2000;89:215-22. 9. Rolland-Cachera MF, Deheeger M, Akrout M, Bellisle F. Influence of macronutrients on adiposity development: a follow up study of nutrition and growth from 10 months to 8 years of age. Int J Obes 1995;19:573-8. 10. Rolland-Cachera MF, Deheeger M, Bellisle F. Increasing prevalence of obesity among 18-year-old males in Sweden: evidence for early determinants. Acta Paediatr 1999;88:365-7.
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11. Axelsson IE, Ivarsson SA, Raiha NC. Protein intake in early infancy: effects on plasma amino acid concentrations, insulin metabolism, and growth. Pediatr Res 1989;26:614-7. 12. Hoppe CF, Møelgaard C, Thomsen BL, Juul A, Michealsen KF. Protein intake at 9 months of age is associated with body size, but not with body fat in 10-year-old Danish children. Am J Clin Nutr 2004;79:494-501. 13. Kramer MS, Guo T, Platt RW, Shapiro S, Collet J-P, Chalmers B, et al. Breastfeeding and infant growth: biology or bias? Pediatrics 2002; 110:343-7. 14. Kramer MS, Guo T, Platt RW, Sevkovskaya Z, Dzikovich I, Collet J-P, et al. Infant growth and health outcomes associated with 3 compared with 6 mo of exclusive breastfeeding. Am J Clin Nutr 2003;78:291-5. 15. Kramer MS, Chalmers B, Hodnett ED, Sevkovskaya Z, Dzikovich I, Shapiro S, et al. Promotion of breastfeeding intervention trial (PROBIT): a randomized trial in the Republic of Belarus. JAMA 2001;285:413-20. 16. Piper S, Parks PL. Use of an intensity ratio to describe breastfeeding exclusivity in a national sample. J Hum Lact 2001;17:227-32. 17. Brown K, Dewey K, Allen L. Complementary Feeding of Young Children in Developing Countries: A Review of Current Scientific Knowledge. Geneva: WHO; 1998. 18. Drewett R, Amatayakul K, Wongsawasdii L, Mangklabruks A, Ruckpaopunt S, Ruangyuttikarn C, et al. Nursing frequency and the energy intake from breast milk and supplementary food in a rural Thai population: a longitudinal study. Eur J Clin Nutr 1993;47:880-91. 19. Kramer MS. Do breast-feeding and delayed introduction of solid foods protect against subsequent obesity? J Pediatr 1981;98:883-7. 20. von Kries R, Koletzko B, Sauerwald T, von Mutius E, Barnert D, Grunert V, et al. Breast feeding and obesity: cross sectional study. BMJ 1999; 319:147-50. 21. Gillman M, Rifas-Shiman S, Camargo C, Berkey C, Frazier A, Rockett H, et al. Risk of overweight among adolescents who were breastfed as infants. JAMA 2001;285:2461-7. 22. Dewey KG, Beaton G, Fjeld C, Lo¨nnerdal B, Reeds P. Protein requirements of infants and children: proceedings of the International Dietary Energy Consultative Group. Eur J Clin Nutr 1996;50(Suppl 1):S119-50. 23. Golding J, Rogers IS, Emmett PM. Association between breastfeeding, child development and behaviour. Early Hum Dev 1997;49:177-84. 24. Anderson J, Johnstone B, Remley D. Breast-feeding and cognitive development: a meta-analysis. Am J Clin Nutr 1999;70:525-35.
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Objective
To examine the effects of formula, other milks, other liquids, cereals, and other solid foods on growth during
infancy.
Study design Observational cohort study nested within a large (n = 17,046), cluster-randomized trial. We compared growth [weight-for-age, length-for-age, and weight-for-length z scores (WAZ, LAZ, WLZ) and head circumference (HC)] during the intervals 1 to 3, 3 to 6, 6 to 9, and 9 to 12 months, using hierarchical multivariate regression to control for size at the beginning of each interval, maternal education, geographic region, and urban versus rural location. Results Mixed BF and formula/other milk were associated with significantly higher (versus breast milk only) LAZ at 1 to 3 months (+0.038 and +0.047, respectively). In the 3- to 6-month interval, mixed BF and formula/other milk led to significantly higher WAZ (+0.125 and +0.139) and LAZ (+0.081 and +0.075), whereas cereal intake was associated with large and highly significant reductions in both measures (20.293 and 20.240) and in HC (20.291 cm). Mixed BF and formula/other milk continued to have positive albeit smaller associations From the Departments of Pediatrics and with WAZ and LAZ in the 6- to 9-month and 9- to 12-month intervals. Conclusions
Our results confirm the growth-accelerating effects of formula and other milks (versus breast milk) on weight and length gain throughout infancy, with a dose-response gradient and largest associations observed at 3 to 6 months. (J Pediatr 2004;145:600-5)
revious studies have consistently reported higher weight and length gains in infants fed formula and/or other milks compared with infants following World Health Organization (WHO)/UNICEF recommendations for prolonged and exclusive breast-feeding.1-6 Downward trajectory is observed in z scores among breast-fed infants, beginning at 2 or 3 months and lasting until approximately 12 months, with considerable but not complete catch-up by 24 months of age. The WHO is currently developing a new international infant growth reference based on infants who follow their feeding recommendations.7,8 Despite the general consistency of the studies, many questions remain unanswered concerning the effects of specific aspects of infant feeding on growth during infancy and beyond. For example, no consistent differences in head circumference (HC) have been identified in breast-fed versus formula-fed infants. Moreover, the sample sizes have been too small to detect independent associations with intake of cereals and other solid foods and of water, juice, and other liquids. Considerable recent interest has also been generated by the suggestion of growth effects attributable to differences in protein content between breast milk and most infant formulas, on the one hand, and the even higher protein concentrations of whole cow’s milk and other milks, on the other. Some investigators have also hypothesized a causal link between protein intake in infancy and long-term risk of adiposity and obesity,9,10 but previous studies have had insufficient sample sizes and durations of follow-up of infants fed either formula or whole cow’s milk to adequately test
P
HC LAZ PROBIT BF
600
Head circumference Length-for-age z score Promotion of Breastfeeding Intervention Trial Breastfeeding
WAZ WLZ WHO
Weight-for-age z score Weight-for-length z score World Health Organization
of Epidemiology and Biostatistics, McGill University Faculty of Medicine, Montreal, Quebec, Canada; Belarussian Maternal and Child Health Research Institute; the Department of Human Nutrition, The Royal Veterinary and Agricultural University, Frederiksberg, Denmark; and the Program of International Nutrition, Department of Nutrition, University of California, Davis, California. *Other members of the Promotion of Breastfeeding Intervention Trial Study Group are Natalia Bogdanovich, MD, PhD, and Gyorgi Shishko, MD, DMSc, Belarussian Maternal and Child Health Research Institute; Stanley Shapiro, PhD, Jean-Paul Collet, MD, PhD, and Thierry Ducruet, MSc, Department of Epidemiology and Biostatistics, McGill University Faculty of Medicine; Beverley Chalmers, PhD, Centre for Research in Women’s Health, Sunnybrook and Women’s College Health Sciences Centre, University of Toronto; Ellen Hodnett, PhD, Faculty of Nursing, University of Toronto; and Irina Mezen, BA, Department of Foreign Relations, Belarussian Ministry of Health. Drs Kramer and Platt are recipients of career investigator awards from the Canadian Institutes of Health Research. Submitted for publication Jan 24, 2003; last revision received Jun 7, 2004; accepted Jun 28, 2004. No reprints available from authors. Please address correspondence to: Michael S. Kramer, MD, The Montreal Children’s Hospital, 2300 Tupper Street, Room T-115, Montreal, Quebec H3H 1P3 Canada. E-mail: michael.kramer@ mcgill.ca. 0022-3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2004.06.069
Table I. Distribution of feeding variables at onset of four age intervals* Feeding variable
1 mo
Milk Breast milk only Mixed breast-feeding Formula/other milk only Water None Any Juice/other liquids None Any Cereal None Any Other solids None Any
3 mo
6 mo
9 mo
13,780 (82.2) 1610 (9.6) 1365 (8.2)
8517 (51.1) 2336 (14.0) 5825 (34.9)
5375 (32.7) 1554 (9.4) 9536 (57.9)
3437 (21.4) 1269 (7.9) 11,387 (70.8)
11,666 (69.6) 5094 (30.4)
11,088 (66.4) 5597 (33.6)
11,209 (68.0) 5272 (32.0)
11,038 (68.2) 5138 (31.8)
14,203 (84.7) 2557 (15.3)
6577 (39.4) 10,108 (60.6)
1943 (11.8) 14,538 (88.2)
1078 (6.7) 15,098 (93.3)
16,758 (100) 2 (0)
16,480 (98.8) 205 (1.2)
3701 (22.5) 12,780 (77.5)
654 (4.0) 15,522 (95.9)
16,569 (98.9) 191 (1.1)
12,964 (77.7) 3721 (22.3)
2426 (14.7) 14,055 (85.3)
476 (2.9) 15,700 (97.1)
Data given as n (%). *Numbers of missing values were 286 to 291 at 1 month, 361 to 368 at 3 months, 565 to 581 at 6 months, and 870 to 953 at 9 months.
Table II. Growth outcomes* in the 1- to 3-month interval Feeding variable Mixed breast-feeding Formula/other milk only Water Juice/other liquids Other solids
WAZ
LAZ
WLZ
HC
20.001 (20.031 to 10.030) 10.038 (10.001 to 10.074) 20.056 (20.097 to 20.014) 20.014 (20.073 to 10.045) 20.010 (20.043 to 10.023) 10.047 (10.007 to 10.087) 20.069 (20.114 to 20.025) 20.064 (20.128 to 20.00003) 20.010 (20.040 to 10.020) 10.002 (20.035 to 10.039) 20.018 (20.060 to 10.023) 10.031 (20.028 to 10.091) 20.005 (20.037 to 10.028) 20.038 (20.077 to 10.002) 10.038 (20.006 to 10.083) 20.017 (20.081 to 10.047) 10.102 (20.003 to 10.208) 20.015 (20.141 to 10.112) 10.136 (20.007 to 10.278) 20.055 (20.259 to 10.148)
*Point estimate (95% CI); WAZ, LAZ, and WLZ are expressed on the z score scale (ie, number of SDs from the reference mean); HC is expressed in centimeters. Feeding variables refer to the beginning of the 1- to 3-month interval, ie, those recorded at 1 month, and all effects of mixed breast-feeding and formula/other milk are based on breast milk only as the reference. All results are adjusted for the anthropometric outcome (WAZ, LAZ, WLZ, or HC) at 1 month, maternal education, region, and urban versus rural location.
this hypothesis. Such a hypothesis is supported by two small feeding studies reporting effects of protein intake on weight gain during infancy.11,12 Finally, previous epidemiologic investigations have been limited by several important methodologic problems common in observational (association) studies of infant feeding and growth, including inadequate control for socioeconomic status, regression to the mean (smaller infants will tend to ‘‘catch up,’’ whereas larger infants will have a tendency to ‘‘catch down’’), and reverse causality (the feeding given is dependent on growth up to the time of the feeding decision, so that feeding can be a consequence of growth, as well as growth being a consequence of feeding).13 Because of these questions and issues, we carried out an observational cohort study nested within a large randomized trial in the Republic of Belarus, in which we attempt to overcome the methodologic problems discussed above. Although we previously reported the results of both Feeding Effects on Growth during Infancy
experimental (as randomized) and observational analyses of infant growth from this study,13,14 those analyses were restricted to associations between growth and the duration and exclusivity of breast-feeding. In the current study, we also examine the effects of formula and whole milks; water, juices, and other liquids; and cereals and other solids within specific intervals during the first year of life.
METHODS The study methods of the Promotion of Breastfeeding Intervention Trial (PROBIT) have been described in detail.13,15 Briefly, 31 maternity hospitals and one each of their affiliated polyclinics (ie, the outpatient clinics in which children are followed for routine health care) were randomly assigned to receive a breast-feeding promotion intervention modeled on the WHO/UNICEF Baby-Friendly Hospital Initiative (experimental group) or to continue the maternity 601
Table III. Growth outcomes* in the 3- to 6-month interval Feeding variable Mixed breast-feeding Formula/other milk only Water Juice/other liquids Cereal Other solids
WAZ
LAZ
WLZ
HC
10.125 (10.096 to 10.154) 10.081 (10.046 to 10.116) 10.054 (10.013 to 10.094) 10.069 (10.016 to 10.122) 10.139 (10.116 to 10.162) 10.075 (10.047 to 10.102) 10.072 (10.040 to 10.104) 10.044 (10.002 to 10.086) 10.013 10.005 20.293 20.022
(20.018 (20.024 (20.386 (20.054
to 10.044) to 10.034) to 20.199) to 10.010)
10.020 10.018 20.240 20.007
(20.019 (20.017 (20.353 (20.046
to 10.058) to 10.054) to 20.127) to 10.032)
20.007 20.016 20.053 20.006
(20.050 (20.056 (20.183 (20.050
to 10.036) to 10.024) to 10.077) to 10.039)
10.023 20.023 20.291 20.054
(20.037 (20.078 (20.463 (20.114
to 10.084) to 10.031) to 20.120) to 10.006)
*Point estimate (95% CI); WAZ, LAZ, and WLZ are expressed on the z score scale (ie, number of SDs from the reference mean); HC is expressed in centimeters. Feeding variables refer to the beginning of the 3- to 6-month interval, ie, those recorded at 3 months, and all effects of mixed breast-feeding and formula/other milk are based on breast milk only as the reference. All results are adjusted for the anthropometric outcome (WAZ, LAZ, WLZ, or HC) at 3 months, maternal education, region, and urban versus rural location.
Table IV. Growth outcomes* in the 6- to 9-month interval Feeding variable Mixed breast-feeding Formula/other milk only Water Juice/other liquids Cereal Other solids
WAZ
LAZ
WLZ
HC
10.032 (10.001 to 10.062) 20.004 (20.044 to 10.035) 10.034 (20.009 to 10.077) 10.024 (20.033 to 10.082) 10.069 (10.049 to 10.088) 10.039 (10.014 to 10.064) 10.058 (10.031 to 10.086) 10.016 (20.021 to 10.052) 10.024 10.013 10.000 20.001
(20.003 (20.019 (20.027 (20.031
to 10.051) to 10.045) to 10.027) to 10.029)
20.001 10.040 10.017 20.002
(20.035 (20.001 (20.017 (20.041
to 10.034) to 10.080) to 10.051) to 10.036)
10.011 20.021 20.007 10.018
(20.025 (20.065 (20.044 (20.024
to 10.046) to 10.024) to 10.030) to 10.060)
10.073 20.016 10.045 20.045
(10.020 (20.076 (20.006 (20.102
to 10.127) to 10.044) to 10.096) to 10.012)
*Point estimate (95% CI); WAZ, LAZ, and WLZ are expressed on the z score scale (ie, number of SDs from the reference mean); HC is expressed in centimeters. Feeding variables refer to the beginning of the 6- to 9-month interval, ie, those recorded at 6 months, and all effects of mixed breast-feeding and formula/other milk are based on breast milk only as the reference. All results are adjusted for the anthropometric outcome (WAZ, LAZ, WLZ, or HC) at 6 months, maternal education, region, and urban versus rural location.
hospital and polyclinic practices in effect at the time of random assignment (control group). A 32nd site was also originally included as part of the study but was excluded because of falsification of outcome data. As then recommended by the WHO, the experimental maternity hospitals and polyclinics encouraged and supported mothers to exclusively breast-feed for 4 to 6 months and to maintain partial breast-feeding to 12 months and beyond. No other specific feeding recommendations were included in the experimental or control interventions. Healthy breast-fed term newborn infants of $37 completed weeks’ gestational age and weighing $2500 g at birth were enrolled during their postpartum hospital stay. Information on infant feeding, illness, and growth was collected at polyclinic visits at 1, 2, 3, 6, 9, and 12 months. A total of 17,046 infants were randomly assigned from the 31 study sites, only 555 (3.3%) of whom were lost to follow-up by 12 months of age. Because differences in growth were not major hypotheses of PROBIT, which focused on reduction in risks of infection and of atopic eczema, no attempts were made to standardize measurements of weight, length, and HC. The outcomes analyzed are based on the Centers for Disease Control/WHO reference, using EpiInfo 2000, and 602
Kramer et al
included the weight-for-age z score (WAZ), length-for-age z score (LAZ), weight-for-length z score (WLZ), and HC. To isolate the effects of several infant feeding variables at specific periods during infancy, we carried out separate analyses within the intervals 1 to 3, 3 to 6, 6 to 9, and 9 to 12 months. Feeding variables were defined at the onset of each of these intervals to protect against reverse causality (ie, change in feeding within the interval in response to changes in weight, length, or HC). To explore effects of differing protein concentrations, milk intake was initially categorized as breast milk only (the reference group), mixed breast-feeding (breast milk plus formula or other milk), formula only, formula plus whole cow’s or other milk, and whole cow’s or other milk only. Except for weight-for-length at 9 to 12 months (see Results), we found no differences in effects of formula versus whole milk intake for any of the growth outcomes within any of the age intervals. The results presented below are therefore based on a trichotomous classification for milk intake: breast milk only, mixed breast-feeding, and formula or other milk only. We also tested more quantitative analytic models based on estimated intake volumes for breast milk, formula, and other milks, with breast milk volume estimates based on the ‘‘breastfeeding intensity ratio’’ of Piper and Parks16 and the breast The Journal of Pediatrics November 2004
Table V. Growth outcomes* in the 9- to 12-month interval Feeding variable Mixed breast-feeding Formula/other milk only Water Juice/other liquids Cereal Other solids
WAZ
LAZ
WLZ
HC
10.036 (10.003 to 10.068) 10.010 (20.032 to 10.052) 10.026 (20.019 to 10.071) 20.034 (20.102 to 10.034) 10.040 (10.021 to 10.060) 10.034 (10.008 to 10.059) 10.051 (10.024 to 10.079) 20.049 (20.090 to 20.008) 10.008 10.026 10.029 20.045
(20.018 (20.016 (20.027 (20.102
to to to to
10.033) 10.069) 10.084) 10.011)
20.011 20.023 10.002 20.082
(20.045 (20.079 (20.070 (20.156
to to to to
10.022) 10.032) 10.075) 20.008)
10.002 10.061 10.052 10.040
(20.032 (10.003 (20.024 (20.039
to to to to
10.037) 10.119) 10.129) 10.119)
10.051 10.063 10.000 20.100
(20.004 (20.027 (20.117 (20.219
to to to to
10.105) 10.153) 10.117) 10.020)
*Point estimate (95% CI); WAZ, LAZ, and WLZ are expressed on the z score scale (ie, number of SDs from the reference mean); HC is expressed in centimeters. Feeding variables refer to the beginning of the 9- to 12-month interval, ie, those recorded at 9 months, and all effects of mixed breast-feeding and formula/other milk are based on breast milk only as the reference. All results are adjusted for the anthropometric outcome (WAZ, LAZ, WLZ, or HC) at 9 months, maternal education, region, and urban versus rural location.
milk volumes at each age reported by Brown et al.17 The results were less consistent than those using the simpler classification; thus the results presented below are primarily based on the latter. Intake of water, juice or other liquids, cereals, and other solids were each dichotomized as any versus none, with none as the reference group. Cereals were not included in the models for 1 to 3 months, since only 2 infants were consuming cereals at 1 month. Data were analyzed using hierarchical linear mixed models (PROC MIXED in SAS). These models included two stratum-specific covariates: (1) western (Grodno or Brest) versus eastern (all other) regions and (2) urban versus rural location of the maternity hospital. Individual-level covariates included the anthropometric outcome at the onset of each age interval (to control for regression to the mean and reverse causality) and maternal education (4 categories). A randomeffects term was also included in the model for maternity hospital at birth, and the individual-level covariates were nested within hospital to account for intraclass correlation of outcomes among infants born at the same maternity hospital. Thus, for each of the intervals studied, the outcome (WAZ, LAZ, WLZHC) was assessed at the end of each interval (ie, at 3, 6, 9, or 12 months) while controlling for the same outcome at the onset of the interval (1, 3, 6, or 9 months) and all of the other stratum and individual-level covariates listed above. This analysis is equivalent to an analysis of increases in anthropometric outcomes (ie, growth velocity) between the beginning and end of each age interval.
RESULTS Table I summarizes the distribution of feeding variables at the onset of the 4 age intervals. These results show the progressive addition/substitution of formula and other milks to breast milk with advancing age, consumption of water by approximately one third of infants at all ages, marked increases in juice intake with age, and the rare consumption of cereals before 6 months and of other solid foods before 3 months. The results of the hierarchical regression analyses are shown in Tables II, III, IV, and V for the 1- to 3-month, 3- to Feeding Effects on Growth during Infancy
6-month, 6- to 9-month, and 9- to 12-month intervals, respectively. In the 1- to 3-month interval (Table II), the main statistically significant effects were observed for LAZ and WLZ, with evidence of a dose-response relation of small magnitude between feeding of milks other than breast milk and higher LAZ and lower WLZ at 3 months of age. The largest effects of the study feeding variables on growth were observed in the 3- to 6-month interval (Table III). Nonbreast milk (formula and/or other milks) was associated with substantial increases in WAZ and smaller increases in LAZ, WLZ, and HC at 6 months. The most striking findings, however, were the large negative associations between cereal intake and WAZ, LAZ, and HC. No significant interactions were observed between cereal intake and breast milk only, mixed breast-feeding, and formula/other milk only (data not shown); in other words, the negative association between cereal intake and growth at 3 to 6 months was of similar magnitude in each of the 3 milk feeding groups. Our more quantitative estimates of milk intake (see Methods) suggested displacement by cereals; the proportion of infants consuming <500 mL of any milk (sum of breast milk, formula, and other milks) at 3 months was 9.3% versus 0.1% in those consuming versus those not consuming cereals at 3 months. Smaller but statistically significant associations between greater weight and length gains and formula/other milk feedings were also observed in the 6- to 9-month and 9- to 12month intervals (Tables IV and V, respectively). Unlike all other growth outcomes at all age intervals studied, we observed larger effects of other milks (versus formula) on WLZ at 9 to 12 months. Mixed breast-feeding was associated with an increase (versus breast milk only) in WLZ of 10.027 (95% CI, 20.018 to 10.071); the corresponding increases were 10.045 (10.016 to 10.074) for formula only, 10.059 (10.016 to 10.101) for formula plus other milk, and 10.064 (10.028 to 10.101) for other milk only. Intake of juices and other liquids was also associated with a significant increase in WLZ at 9 to 12 months. A statistically significantly larger increase in HC between 6 and 9 months was observed among infants who received water feedings at 6 months (Table IV). The increase 603
in head circumference between 9 and 12 months was statistically significantly smaller among infants who received only formula or other milk as the sole source of milk feedings at 9 months (Table V).
DISCUSSION Our results confirm the large and increasing body of evidence indicating that formula and other milks accelerate both weight gain and length gain during infancy, particularly after 3 months of age.1-6 Our large sample size enabled us to demonstrate a dose-response relation between non-breast milk or formula intake and both length and weight gain and to identify the 3- to 6-month interval as the time period in which these effects are largest. We also observed strong negative associations between cereal intake and length, weight, and HC gains in the 3- to 6-month interval. Previous studies have documented a reduction in breast milk intake in infants offered cereals and other solid foods during this critical time period.17,18 Our results confirm these negative effects and extend them to infants receiving formula and other milks as well. The energy, protein, and micronutrient content of most cereals are inferior to those of breast milk, formula, and other milks, and our results suggesting displacement of milk feeding by cereals during the 3- to 6-month interval may explain the observed adverse effect on growth. Another potential explanation for the strong negative associations with cereal intake is the high phytate content of many cereals, which can reduce zinc absorption and thereby limit growth during this age period.17 The negative associations we observed between receipt of cereals and growth between 3 and 6 months, however, are based on a very small proportion of infants who received cereals at 3 months (1.2%, see Table I) and should therefore be interpreted cautiously. Moreover, we have no information on the reasons for giving cereals, and thus the association we observed between cereal intake and low total milk volumes at 3 months could be explained by mothers’ attempts to compensate for low milk intakes by giving cereals rather than an adverse effect of cereal consumption on milk intake. Finally, the cereals given to infants in Belarus at the time of this trial were those traditionally consumed by adults, not the micronutrient-fortified, finely powdered product used in most Western countries. Thus, the effects of cereals we observed may not be generalizable to other settings. Some epidemiologic studies have suggested that prolonged and exclusive breast-feeding is associated with a reduced long-term risk of obesity,19-21 suggesting that these early differences in growth might ‘‘program’’ appetite, adipocyte proliferation, or energy metabolism. Longer-term follow-up of our PROBIT cohort will be required to assess whether the effects of formula and other milk on weight and length growth during infancy will persist and whether they are associated with obesity or other health outcomes later in childhood and adulthood. Although our sample size was large, we found no consistent differences in growth among infants receiving whole cow’s milk versus formula, despite the much higher 604
Kramer et al
concentration of protein in whole cow’s milk (approximately 4 g/100 mL) than in formula. Most formulas in the Republic of Belarus contain between 1.6 and 1.7 g/100 mL of protein, and thus our findings do not provide strong support for the hypothesis that protein intake is a major determinant of growth and adiposity, at least during infancy.9,10 We did, however, observe differences in WLZ at 9 to 12 months consistent with a dose-response effect of protein intake. The absence of such differences at other ages and for other growth outcomes suggests that these findings may have arisen by chance, although the lower protein requirements (in g/kg per day) at this age provides one potential mechanism for a true biological effect of higher protein intake on adiposity.22 We found no consistent effects of formula and other milks, cereals, or other solids or liquids on head growth. Slight increases in HC in infants who received formula or other milks between 3 and 6 months appeared to be counterbalanced by negative effects of similar magnitude between 9 and 12 months. Longer-term follow-up will be required to determine whether prolonged and exclusive breast-feeding has longerterm effects on head growth and whether those effects are associated with previously reported advances in neurocognitive development among such infants.23,24 Although we found an increase in HC at 9 months among infants receiving water feedings at 9 months, the small magnitude of the effect (0.073 cm) and the absence of effects of water on other measures or at other ages suggest that this finding is likely to have occurred by chance. Several limitations of our study require emphasis. This remains an observational (cohort) analysis and therefore does not benefit from PROBIT’s randomized trial design. Despite our best attempts to control for individual- and regional-level confounding variables, regression to the mean, and reverse causality, residual confounding (eg, caused by unmeasured differences in parental body mass index) and selection bias cannot be excluded in such an observational analysis. None of the specific feeding variables studied here (formula/other milk, water, juice, or other liquids, cereals, or other solids) were part of the randomized intervention, which promoted exclusive and prolonged breast-feeding, as advocated by WHO and UNICEF. Thus, an intention-to-treat analysis based on randomization cannot shed light on these nonrandomized feeding choices. Second, as mentioned in Methods, the primary outcomes in PROBIT related to infection and atopic eczema, not infant growth. Anthropometric measurements were carried out by 31 different pediatricians, with no attempt to standardize measuring instruments or measurement methods. The absence of such standardization, however, should increase random (nondifferential) error and therefore attenuate associations with infant feeding and other potential determinants. Finally, the long-term consequences of the effects we have observed remain uncertain. In particular, it will be important to determine whether these effects persist in terms of risk of obesity, age at puberty, and adult stature; whether they are associated with differences in neurocognitive development; and whether they are associated with risk factors The Journal of Pediatrics November 2004
for chronic adult diseases such as type 2 diabetes, hypertension, and coronary heart disease. Some of these consequences are currently under investigation as we follow up PROBIT children at the age of 6.5 years.
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11. Axelsson IE, Ivarsson SA, Raiha NC. Protein intake in early infancy: effects on plasma amino acid concentrations, insulin metabolism, and growth. Pediatr Res 1989;26:614-7. 12. Hoppe CF, Møelgaard C, Thomsen BL, Juul A, Michealsen KF. Protein intake at 9 months of age is associated with body size, but not with body fat in 10-year-old Danish children. Am J Clin Nutr 2004;79:494-501. 13. Kramer MS, Guo T, Platt RW, Shapiro S, Collet J-P, Chalmers B, et al. Breastfeeding and infant growth: biology or bias? Pediatrics 2002; 110:343-7. 14. Kramer MS, Guo T, Platt RW, Sevkovskaya Z, Dzikovich I, Collet J-P, et al. Infant growth and health outcomes associated with 3 compared with 6 mo of exclusive breastfeeding. Am J Clin Nutr 2003;78:291-5. 15. Kramer MS, Chalmers B, Hodnett ED, Sevkovskaya Z, Dzikovich I, Shapiro S, et al. Promotion of breastfeeding intervention trial (PROBIT): a randomized trial in the Republic of Belarus. JAMA 2001;285:413-20. 16. Piper S, Parks PL. Use of an intensity ratio to describe breastfeeding exclusivity in a national sample. J Hum Lact 2001;17:227-32. 17. Brown K, Dewey K, Allen L. Complementary Feeding of Young Children in Developing Countries: A Review of Current Scientific Knowledge. Geneva: WHO; 1998. 18. Drewett R, Amatayakul K, Wongsawasdii L, Mangklabruks A, Ruckpaopunt S, Ruangyuttikarn C, et al. Nursing frequency and the energy intake from breast milk and supplementary food in a rural Thai population: a longitudinal study. Eur J Clin Nutr 1993;47:880-91. 19. Kramer MS. Do breast-feeding and delayed introduction of solid foods protect against subsequent obesity? J Pediatr 1981;98:883-7. 20. von Kries R, Koletzko B, Sauerwald T, von Mutius E, Barnert D, Grunert V, et al. Breast feeding and obesity: cross sectional study. BMJ 1999; 319:147-50. 21. Gillman M, Rifas-Shiman S, Camargo C, Berkey C, Frazier A, Rockett H, et al. Risk of overweight among adolescents who were breastfed as infants. JAMA 2001;285:2461-7. 22. Dewey KG, Beaton G, Fjeld C, Lo¨nnerdal B, Reeds P. Protein requirements of infants and children: proceedings of the International Dietary Energy Consultative Group. Eur J Clin Nutr 1996;50(Suppl 1):S119-50. 23. Golding J, Rogers IS, Emmett PM. Association between breastfeeding, child development and behaviour. Early Hum Dev 1997;49:177-84. 24. Anderson J, Johnstone B, Remley D. Breast-feeding and cognitive development: a meta-analysis. Am J Clin Nutr 1999;70:525-35.
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