Weight Gain in the First Week of Life and Overweight in Adulthood
http://www.100md.com
循环学杂志 2005年第4期
the Division of Gastroenterology and Nutrition (N.S., V.A.S.), The Children’s Hospital of Philadelphia, Philadelphia, Pa
Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology (N.S., A.B.T., J.Z., R.S., B.L.S.), University of Pennsylvania School of Medicine, Philadelphia, Pa
The Fomon Infant Nutrition Unit (S.E.N., E.E.Z.), University of Iowa, Iowa City, Iowa.
Abstract
Background— Successful prevention of obesity and related cardiovascular risk factors requires a clear understanding of its determinants over the life course. Rapid infancy weight gain is associated with childhood obesity, whereas low infancy weight is associated with coronary heart disease. Our aim was to identify during which periods in infancy weight gain is associated with adult obesity.
Methods and Results— A cohort of European American formula-fed subjects, measured on 7 occasions during infancy as part of several infant formula studies, were contacted at age 20 to 32 years, when they reported usual adult weight and height. A life-course plot was used to identify critical periods of weight gain associated with adulthood overweight (body mass index 25 kg/m2). These associations were tested with logistic regressions. Data were available for 653 subjects (72% of eligible subjects). Approximately 32% of them were overweight adults. The period between birth and age 8 days was identified as potentially critical. After adjustment for important confounding factors, weight gain during the first week of life was associated with adulthood overweight status (OR for each 100-g increase 1.28, 95% CI 1.08 to 1.52), as was weight gain during the first 112 days of life (OR 1.04, 95% CI 1.01 to 1.08). Similar results were obtained after standardization with z scores from a reference population.
Conclusions— In formula-fed infants, weight gain during the first week of life may be a critical determinant for the development of obesity several decades later. These results contribute to the understanding of chronic disease programming and suggest new approaches to obesity prevention.
Key Words: risk factors ; infant formula ; obesityfollow-up studiespediatrics
Introduction
The prevalence of obesity is increasing in the United States and globally among adults and children.1–5 Because obesity is a major risk factor for cardiovascular diseases, evidence-based strategies to prevent obesity are increasingly urgent priorities to prevent cardiovascular diseases. Owing to renewed interest in a life-course approach to chronic disease epidemiology and prevention,6 the potential for interventions during critical periods has been explored in several observational studies.7,8 In particular, our group and others have shown that a rapid weight gain in infancy is associated with the development of childhood obesity in populations of European, African, and Asian ancestry.9–16 We have also shown that rapid weight gain in the first 4 months of life is associated with obesity in a sample of young black adults,17 whereas others have shown a similar association in young Swiss adults.18 It is unclear, however, whether this association remains present later in adulthood and which specific period in infancy is critical for the long-term risk of obesity.
Another body of research has addressed the association of early growth patterns with cardiovascular risk factors and diseases. Although low birth weight has been associated consistently with elevated blood pressure and coronary heart disease,19–22 the association of infancy weight gain with cardiovascular risk factors and diseases remains controversial. Coronary heart disease has been associated with low weight during infancy in observational studies,23,24 whereas experimental studies in human and animals have described increased cardiovascular risk factors with rapid weight gain during early infancy.25–29 Because infancy weight gain is a potential target for preventive interventions, it is critical to understand better the association between infancy growth patterns and the development of cardiovascular risk factors, including obesity.
Methods
This is a secondary analysis of data from a cohort of subjects who, as infants, participated in a number of feeding studies, both published34,35 and unpublished, that involved a number of different cow milk–based and soy-based formulas and who later participated in a follow-up study designed to investigate the effect of these formulas on pubertal development and reproductive history.36 Participants in the original cohort study were healthy infants born between 1965 and 1978 in the region of Iowa City, Iowa, whose mothers elected not to breastfeed. The source population was all infants born at or above 2500 g living in and around Iowa City at the time of the study. Recruitment was by word of mouth or by visits to maternity wards in the area, and no attempt was made to document the response rate for recruitment of the original cohort. With few exceptions, all subjects were of European descent, which reflects the racial composition of the area at that time. The subjects were enrolled at age 8 days and followed up to age 112 days as part of several nonrandomized studies of infant feeding and growth. One of the inclusion criteria for the original study was no breastfeeding before enrollment, not even for 1 day. Therefore, none of the infants were breastfed before or during the study. Depending on the study taking place at the time of their birth, they were assigned to the infant formula under study at that time. Although the subjects were not strictly randomized to soy-based or cow milk–based formulas, they were assigned the formula in use at the research unit within 2 days of the time of their enrollment into the study (age 8 days), without taking into account the infant’s characteristics or the parents’ choice. Once assigned to a formula, the same formula was fed during the entire study period. No complementary food was allowed before 28 days of life, but, at the parents’ discretion, selected complementary foods were allowed afterward, although not encouraged: after 28 days of life, oatmeal with bananas and applesauce; after 56 days of life, pears; and after 84 days of life, applesauce or bananas.34 Some parents introduced other complementary foods not included in the protocol. Because intake of complementary foods was generally small and not completely available, this variable was not included in the analyses. The infants’ weights were measured at age 8, 14, 28, 42, 56, 84, and 112 days as described previously.37 Birth weight was reported by the mother at enrollment.
Subjects eligible for the adult follow-up study36 were those who received only soy-based or cow milk–based formula, completed the 112 days of the infant study, were not adopted, were not from foreign countries, were not disabled, and were still alive in 1999. A national search was conducted to locate the 952 original cohort subjects using contact information from the original study and public records. A lengthy telephone questionnaire was administered by trained interviewers in 1999 to 2000 to assess pubertal and reproductive history,36 as well as usual weight and height. Other variables of interest assessed by telephone interview included age at interview, parental weight category, and subject income category.
To adjust weight during infancy for physiological growth and gender differences, the weight-for-age z score (WAZ) in SD units was calculated by the LMS method38 at each measurement point in infancy with a reference population of US children.39 The LMS method uses 3 parameters (L for the power in the Box-Cox transformation, M for the median, and S for the generalized coefficient of variation) to determine an age- and gender-specific z-score value for a subject’s weight.38 This method is used by the Centers for Disease Control and Prevention (CDC) to generate z scores based on US population data.39 Because LMS parameters are only available at 1-month increments, values were generated for age 8, 14, 28, 42, 56, 84, and 112 days assuming a linear relation of the LMS parameters between each month point. Absolute weight gains from birth to 8 days and birth to 112 days of life were calculated as the absolute difference between the 2 weights. Change in z score was defined as the difference in WAZ between birth and age 8 days and to age 112 days, respectively. Body mass index (BMI) in adulthood was calculated as self-reported usual weight in kilograms divided by self-reported adult height in meters squared. The usual definition of overweight is a BMI 25 kg/m2 but <30 kg/m2. To simplify the nomenclature, for the present study, we defined subjects as overweight if they had a BMI 25 kg/m2 and as obese if they had a BMI 30 kg/m2. According to this definition, all obese subjects were also overweight. The subjects’ parents’ weight status was reported by the subject during the interview and classified as overweight if the parent was described as somewhat or extremely overweight and nonoverweight if the parent was described as slim or average weight. The main exposure (absolute weight gain and change in z score from birth to age 8 days and birth to age 112 days), the main outcome (adult overweight status), and possible confounding variables (gender, type of infant formula used, age at interview, maternal and paternal weight status, and subject’s income) were explored graphically, tested for normality, and described by use of medians, percentiles, and proportions as appropriate. Subjects with complete data were compared with other subjects by 2 or t test as appropriate. To assess which, if any, period of weight gain in early infancy was associated with adulthood weight status, a life-course plot was constructed with adulthood overweight status as the outcome. As described in detail by Cole,40 this method uses a logistic regression of the outcome (here, adulthood overweight status) with WAZ at each time point during growth as independent variables, adjusted for each other and for important confounding variables selected a priori on the basis of the existing literature. The ;-coefficients are then plotted against time to visually assess which period of change in WAZ (slope of the life-course plot) corresponds to a sensitive or critical period for the development of the outcome. The association of weight gain during the sensitive periods and the possible confounding variables with adulthood overweight status was tested by simple logistic regression or 2 test as appropriate. Possible interactions of gender or formula type in the association between infancy weight gain and adulthood weight status were tested with an interaction factor in the logistic model. To test the association of infancy weight gain with adulthood weight status, while adjusting for confounding factors selected a priori on the basis of the existing literature, a multiple logistic regression model was used. Stata 7.0 was used for all statistical analyses.41 All significance tests were 2-sided, and a probability value <0.05 was considered significant. This study was approved by the Institutional Review Board of The Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine, and the subjects gave informed consent.
Results
As reported previously,36 among the 952 subjects of the original cohort, 904 were eligible for the adult follow-up study, whereas the others were ineligible because they received both soy- and cow milk–based formula (n=26), were deceased (n=10), were from countries other than the United States (n=7), were disabled (n=3), or were adopted (n=2). Among the 904 eligible subjects, 811 were interviewed, 51 were not located, and 42 refused to participate. Of the 811 subjects interviewed, 653 had complete data on infant growth and adult weight status. These 653 subjects (72% of the eligible subjects) constitute the sample studied in the present analysis (Table 1) and were not different at baseline from the subjects of the original cohort who were not analyzed for gender distribution (P=0.7), formula assignment (P=0.8), or birth weight (P=0.7). Most variables were not normally distributed and are consequently summarized with medians and percentiles. The prevalence of obesity was low in this sample compared with the general population of adults of the same age group and race,1,5 with only 37 subjects (5.7%) reporting a usual weight and height that corresponded to obesity (BMI 30 kg/m2). Although analyses that used obesity as an outcome were of interest, the small number of obese subjects did not allow for meaningful analyses. Therefore, all further analyses are reported with overweight status (BMI 25 kg/m2, 32.3% of subjects) as outcome.
Discussion
The main finding of the present study was that weight gain during the first week of life in healthy, European American, formula-fed infants was associated with overweight status 2 to 3 decades later. This finding is important, not so much to predict which infants are at risk for becoming overweight adults, but more to understand the importance of the human physiology of programming during short early-life periods on the development of chronic disease over the life course. These results also point to new potential targets for obesity prevention. The association of absolute weight gain in the first week of life in formula-fed infants with adulthood overweight status was clinically significant. After adjustment for important confounding factors, each 100-g increase in absolute weight gain during this period was associated with a 28% increase in the risk of becoming an overweight adult (95% CI 8% to 52%). Because the weight gain during the first week of life ranged in this sample from 0 to 400 g, a 100-g difference is within the range of normal weight gain. From this observational study, it is unclear whether this association was causal, due to unmeasured confounding factors, or whether both weight gain in the first week of life and adult overweight were determined by underlying factors, such as genetic predisposition to obesity expressed early in life. However, an intervention study of premature infants randomized for 4 weeks to usual or enriched nutrition that resulted in increased weight gain suggests that the impact of growth patterns in early postnatal life on the development of cardiovascular risk factors, such as high blood pressure, insulin resistance, and endothelial function, may be at least partially causal.25–27,43 Additionally, several studies in animal models have demonstrated that overfeeding in the first few days of life led to long-term obesity, perhaps by programming of the developing brain or the endocrine system.28,29,44,45 These results should be contrasted with other studies showing an increased risk for coronary heart disease with low weight at birth and during infancy.20,23,24 Most of these studies, however, did not specifically test the association of coronary heart disease with patterns of weight gains but rather with body weight at one point in infancy, which depends both on previous weight and weight gain. In interpreting the results of the present study, it should be emphasized that in humans, the weight change from birth to age 8 days cannot be considered as a true "growth parameter." Weight changes during this period mainly reflect the amount of formula ingested, which in turn could be influenced by a number of factors, including minor illnesses, perinatal depression, or slow meconium passage. Also, weight changes during this period are likely influenced by the degree of reduction in total body water, which is affected by mild overhydration or underhydration at the time of delivery. If confirmed by others and if in part causal, the present findings may lead to short interventions in infants to prevent long-term development of obesity. Because the prevalence of obesity continues to increase worldwide and its prevention and treatment are frequently unsuccessful,1–5 new strategies based on a life-course approach may be useful to prevent obesity and related cardiovascular risk factors.
The present study confirms the previously reported associations of adult overweight status with weight gain in the first few months of life.17,18 The life-course plot (Figure 2), however, suggests that the first week of life may be particularly sensitive. The present study also confirms the association of adulthood overweight with birth weight,21,22 maternal overweight,46 and increasing age of the subject.1 Unlike what has been described in a nationally representative European American sample of the same age group, in the present sample, women were less likely to be overweight than men, and overweight was not associated with income.47 Some of the adjusted analyses, but not the unadjusted analysis, revealed an increased risk for overweight in individuals assigned to the soy-based compared with the cow milk–based formula (Tables 2 and 3). This incidental finding should be taken with caution because of the inconsistency in results between analytical models and the borderline level of statistical significance, but it suggests that soy-based formula should be further investigated as a possible risk factor for overweight.
The present study had some limitations. Early cardiovascular disease could not be assessed by telephone interview in this sample of relatively young adults. Therefore, the present data do not provide information on the cardiovascular consequences of the association between early infancy weight gain and adulthood obesity. Another limitation of the present study was the low prevalence of obesity and overweight. The prevalence of overweight was lower in this sample (32%) than in the general population of European Americans in this age range (55%) based on measured rather than self-reported weight and height,5 which suggests underreporting of overweight in the present sample. Because it is unlikely that the presence or magnitude of underreporting was associated with absolute weight gain during the first week of life, this limitation likely resulted in a nondifferential misclassification, thus resulting in a bias toward the null hypothesis and an underestimation of the true effect size. Alternatively, the low prevalence of overweight and obesity in this sample reflects the relatively high socioeconomic status of the study subjects,37 because the source population included many infants born to students and young faculty at the University of Iowa. The relatively small number of subjects classified as obese (BMI 30 kg/m2) was insufficient to perform meaningful analyses, and the analyses are reported with overweight status (BMI 25 kg/m2) as the outcome. Although not statistically significant, the direction of the associations was similar with the small number of obese subjects (data not shown). Birth weight was reported by the mother, but a significant reporting error is unlikely because it was assessed only 8 days after delivery. Should such reporting error have occurred, it would be unlikely to be associated with the outcome, which took place several decades later. Therefore, such bias would also have led to an underestimation of the effect size. Introduction of complementary foods after 28 days of life may have confounded the association of adult overweight with weight gain during the first 112 days of life but not with weight gain in the first week of life. The use of z scores obtained from smoothed cross-sectional reference data to model longitudinal data are controversial and has its limitations. These limitations, in the models that used z scores, may explain in part the large differences in ORs between the unadjusted and adjusted analyses and why, in the unadjusted analysis, the association of change in z score with adult overweight was not significant; however, after adjustment for important confounding factors, the results with absolute value of weight change or z scores were similar. Because of the characteristics of the sample, the present findings cannot be generalized to non-European American individuals or to breastfed infants, and our conclusions only apply to formula-fed infants. The relatively low rate of complete data (72%) was also of concern but is not unusual for a birth cohort with follow-up over 3 decades.
The study also had unique strengths. We used a life-course plot to identify potentially sensitive or critical periods of weight gain for the development of obesity40 rather than arbitrarily chosen periods. By plotting the standardized ;-coefficients of a multiple logistic regression that included several WAZ values measured during infancy, adjusted for each other and for important confounding variables, this method is the first, to the best of our knowledge, to allow identification, based on data, of potentially critical periods of weight gain for adult outcomes. One of the limitations of this method is the possibility that the addition of an observation between 2 observations may modify the observed slope and therefore the interpretation of the plot. Consequently, to provide useful information, this method assumes that measurements are close to one another, as described in detail by Cole.40 In the present study, this assumption was met, and therefore this limitation is unlikely to have played an important role. Compared with breastfeeding, formula feeding has been associated with more rapid absolute weight gain in early infancy30,31 and with obesity in adolescence,32,33 but because the present study was limited to exclusively formula-fed subjects, our finding cannot be explained by infant feeding mode. Additionally, all infant measurements other than birth weight were performed prospectively as part of a rigorous research protocol.
In conclusion, the present study demonstrates a significant increase in the risk of overweight status in adulthood associated with increasing weight gain during the first week of life. This finding may have important research and public health implications at a time when obesity prevention is becoming a global public health priority to reduce cardiovascular and other obesity-related diseases.
Acknowledgments
Data collection for this study was originally funded by National Institutes of Health (NIH) contract N01-HD-8-3279 and a grant from the Infant Formula Council (now the International Formula Council). Dr Stettler is funded in part by NIH grant K23-RR-016073. The authors are thankful to the study subjects, their families, and the staff of the Fomon Infant Nutrition Unit at the University of Iowa, the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania, and The Children’s Hospital of Philadelphia.
Disclosure
The Fomon Infant Nutrition Unit receives research grants from and conducts clinical trials funded by Ross Product Division, Nestle, and Mead Johnson Nutritional. Dr Ziegler has received honoraria for speaking from the same companies, mostly in continuing education settings. In the past, Dr Stallings received an unrestricted educational and research grant from Bristol Myers Squibb for The Children’s Hospital of Philadelphia Nutrition Center.
Footnotes
Presented in part at the 3rd Conference of Epidemiological Longitudinal Studies in Europe, Bristol, United Kingdom, September 22–24, 2004, and at the North American Association for the Study of Obesity, Las Vegas, Nev, November 14–18, 2004.
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Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology (N.S., A.B.T., J.Z., R.S., B.L.S.), University of Pennsylvania School of Medicine, Philadelphia, Pa
The Fomon Infant Nutrition Unit (S.E.N., E.E.Z.), University of Iowa, Iowa City, Iowa.
Abstract
Background— Successful prevention of obesity and related cardiovascular risk factors requires a clear understanding of its determinants over the life course. Rapid infancy weight gain is associated with childhood obesity, whereas low infancy weight is associated with coronary heart disease. Our aim was to identify during which periods in infancy weight gain is associated with adult obesity.
Methods and Results— A cohort of European American formula-fed subjects, measured on 7 occasions during infancy as part of several infant formula studies, were contacted at age 20 to 32 years, when they reported usual adult weight and height. A life-course plot was used to identify critical periods of weight gain associated with adulthood overweight (body mass index 25 kg/m2). These associations were tested with logistic regressions. Data were available for 653 subjects (72% of eligible subjects). Approximately 32% of them were overweight adults. The period between birth and age 8 days was identified as potentially critical. After adjustment for important confounding factors, weight gain during the first week of life was associated with adulthood overweight status (OR for each 100-g increase 1.28, 95% CI 1.08 to 1.52), as was weight gain during the first 112 days of life (OR 1.04, 95% CI 1.01 to 1.08). Similar results were obtained after standardization with z scores from a reference population.
Conclusions— In formula-fed infants, weight gain during the first week of life may be a critical determinant for the development of obesity several decades later. These results contribute to the understanding of chronic disease programming and suggest new approaches to obesity prevention.
Key Words: risk factors ; infant formula ; obesityfollow-up studiespediatrics
Introduction
The prevalence of obesity is increasing in the United States and globally among adults and children.1–5 Because obesity is a major risk factor for cardiovascular diseases, evidence-based strategies to prevent obesity are increasingly urgent priorities to prevent cardiovascular diseases. Owing to renewed interest in a life-course approach to chronic disease epidemiology and prevention,6 the potential for interventions during critical periods has been explored in several observational studies.7,8 In particular, our group and others have shown that a rapid weight gain in infancy is associated with the development of childhood obesity in populations of European, African, and Asian ancestry.9–16 We have also shown that rapid weight gain in the first 4 months of life is associated with obesity in a sample of young black adults,17 whereas others have shown a similar association in young Swiss adults.18 It is unclear, however, whether this association remains present later in adulthood and which specific period in infancy is critical for the long-term risk of obesity.
Another body of research has addressed the association of early growth patterns with cardiovascular risk factors and diseases. Although low birth weight has been associated consistently with elevated blood pressure and coronary heart disease,19–22 the association of infancy weight gain with cardiovascular risk factors and diseases remains controversial. Coronary heart disease has been associated with low weight during infancy in observational studies,23,24 whereas experimental studies in human and animals have described increased cardiovascular risk factors with rapid weight gain during early infancy.25–29 Because infancy weight gain is a potential target for preventive interventions, it is critical to understand better the association between infancy growth patterns and the development of cardiovascular risk factors, including obesity.
Methods
This is a secondary analysis of data from a cohort of subjects who, as infants, participated in a number of feeding studies, both published34,35 and unpublished, that involved a number of different cow milk–based and soy-based formulas and who later participated in a follow-up study designed to investigate the effect of these formulas on pubertal development and reproductive history.36 Participants in the original cohort study were healthy infants born between 1965 and 1978 in the region of Iowa City, Iowa, whose mothers elected not to breastfeed. The source population was all infants born at or above 2500 g living in and around Iowa City at the time of the study. Recruitment was by word of mouth or by visits to maternity wards in the area, and no attempt was made to document the response rate for recruitment of the original cohort. With few exceptions, all subjects were of European descent, which reflects the racial composition of the area at that time. The subjects were enrolled at age 8 days and followed up to age 112 days as part of several nonrandomized studies of infant feeding and growth. One of the inclusion criteria for the original study was no breastfeeding before enrollment, not even for 1 day. Therefore, none of the infants were breastfed before or during the study. Depending on the study taking place at the time of their birth, they were assigned to the infant formula under study at that time. Although the subjects were not strictly randomized to soy-based or cow milk–based formulas, they were assigned the formula in use at the research unit within 2 days of the time of their enrollment into the study (age 8 days), without taking into account the infant’s characteristics or the parents’ choice. Once assigned to a formula, the same formula was fed during the entire study period. No complementary food was allowed before 28 days of life, but, at the parents’ discretion, selected complementary foods were allowed afterward, although not encouraged: after 28 days of life, oatmeal with bananas and applesauce; after 56 days of life, pears; and after 84 days of life, applesauce or bananas.34 Some parents introduced other complementary foods not included in the protocol. Because intake of complementary foods was generally small and not completely available, this variable was not included in the analyses. The infants’ weights were measured at age 8, 14, 28, 42, 56, 84, and 112 days as described previously.37 Birth weight was reported by the mother at enrollment.
Subjects eligible for the adult follow-up study36 were those who received only soy-based or cow milk–based formula, completed the 112 days of the infant study, were not adopted, were not from foreign countries, were not disabled, and were still alive in 1999. A national search was conducted to locate the 952 original cohort subjects using contact information from the original study and public records. A lengthy telephone questionnaire was administered by trained interviewers in 1999 to 2000 to assess pubertal and reproductive history,36 as well as usual weight and height. Other variables of interest assessed by telephone interview included age at interview, parental weight category, and subject income category.
To adjust weight during infancy for physiological growth and gender differences, the weight-for-age z score (WAZ) in SD units was calculated by the LMS method38 at each measurement point in infancy with a reference population of US children.39 The LMS method uses 3 parameters (L for the power in the Box-Cox transformation, M for the median, and S for the generalized coefficient of variation) to determine an age- and gender-specific z-score value for a subject’s weight.38 This method is used by the Centers for Disease Control and Prevention (CDC) to generate z scores based on US population data.39 Because LMS parameters are only available at 1-month increments, values were generated for age 8, 14, 28, 42, 56, 84, and 112 days assuming a linear relation of the LMS parameters between each month point. Absolute weight gains from birth to 8 days and birth to 112 days of life were calculated as the absolute difference between the 2 weights. Change in z score was defined as the difference in WAZ between birth and age 8 days and to age 112 days, respectively. Body mass index (BMI) in adulthood was calculated as self-reported usual weight in kilograms divided by self-reported adult height in meters squared. The usual definition of overweight is a BMI 25 kg/m2 but <30 kg/m2. To simplify the nomenclature, for the present study, we defined subjects as overweight if they had a BMI 25 kg/m2 and as obese if they had a BMI 30 kg/m2. According to this definition, all obese subjects were also overweight. The subjects’ parents’ weight status was reported by the subject during the interview and classified as overweight if the parent was described as somewhat or extremely overweight and nonoverweight if the parent was described as slim or average weight. The main exposure (absolute weight gain and change in z score from birth to age 8 days and birth to age 112 days), the main outcome (adult overweight status), and possible confounding variables (gender, type of infant formula used, age at interview, maternal and paternal weight status, and subject’s income) were explored graphically, tested for normality, and described by use of medians, percentiles, and proportions as appropriate. Subjects with complete data were compared with other subjects by 2 or t test as appropriate. To assess which, if any, period of weight gain in early infancy was associated with adulthood weight status, a life-course plot was constructed with adulthood overweight status as the outcome. As described in detail by Cole,40 this method uses a logistic regression of the outcome (here, adulthood overweight status) with WAZ at each time point during growth as independent variables, adjusted for each other and for important confounding variables selected a priori on the basis of the existing literature. The ;-coefficients are then plotted against time to visually assess which period of change in WAZ (slope of the life-course plot) corresponds to a sensitive or critical period for the development of the outcome. The association of weight gain during the sensitive periods and the possible confounding variables with adulthood overweight status was tested by simple logistic regression or 2 test as appropriate. Possible interactions of gender or formula type in the association between infancy weight gain and adulthood weight status were tested with an interaction factor in the logistic model. To test the association of infancy weight gain with adulthood weight status, while adjusting for confounding factors selected a priori on the basis of the existing literature, a multiple logistic regression model was used. Stata 7.0 was used for all statistical analyses.41 All significance tests were 2-sided, and a probability value <0.05 was considered significant. This study was approved by the Institutional Review Board of The Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine, and the subjects gave informed consent.
Results
As reported previously,36 among the 952 subjects of the original cohort, 904 were eligible for the adult follow-up study, whereas the others were ineligible because they received both soy- and cow milk–based formula (n=26), were deceased (n=10), were from countries other than the United States (n=7), were disabled (n=3), or were adopted (n=2). Among the 904 eligible subjects, 811 were interviewed, 51 were not located, and 42 refused to participate. Of the 811 subjects interviewed, 653 had complete data on infant growth and adult weight status. These 653 subjects (72% of the eligible subjects) constitute the sample studied in the present analysis (Table 1) and were not different at baseline from the subjects of the original cohort who were not analyzed for gender distribution (P=0.7), formula assignment (P=0.8), or birth weight (P=0.7). Most variables were not normally distributed and are consequently summarized with medians and percentiles. The prevalence of obesity was low in this sample compared with the general population of adults of the same age group and race,1,5 with only 37 subjects (5.7%) reporting a usual weight and height that corresponded to obesity (BMI 30 kg/m2). Although analyses that used obesity as an outcome were of interest, the small number of obese subjects did not allow for meaningful analyses. Therefore, all further analyses are reported with overweight status (BMI 25 kg/m2, 32.3% of subjects) as outcome.
Discussion
The main finding of the present study was that weight gain during the first week of life in healthy, European American, formula-fed infants was associated with overweight status 2 to 3 decades later. This finding is important, not so much to predict which infants are at risk for becoming overweight adults, but more to understand the importance of the human physiology of programming during short early-life periods on the development of chronic disease over the life course. These results also point to new potential targets for obesity prevention. The association of absolute weight gain in the first week of life in formula-fed infants with adulthood overweight status was clinically significant. After adjustment for important confounding factors, each 100-g increase in absolute weight gain during this period was associated with a 28% increase in the risk of becoming an overweight adult (95% CI 8% to 52%). Because the weight gain during the first week of life ranged in this sample from 0 to 400 g, a 100-g difference is within the range of normal weight gain. From this observational study, it is unclear whether this association was causal, due to unmeasured confounding factors, or whether both weight gain in the first week of life and adult overweight were determined by underlying factors, such as genetic predisposition to obesity expressed early in life. However, an intervention study of premature infants randomized for 4 weeks to usual or enriched nutrition that resulted in increased weight gain suggests that the impact of growth patterns in early postnatal life on the development of cardiovascular risk factors, such as high blood pressure, insulin resistance, and endothelial function, may be at least partially causal.25–27,43 Additionally, several studies in animal models have demonstrated that overfeeding in the first few days of life led to long-term obesity, perhaps by programming of the developing brain or the endocrine system.28,29,44,45 These results should be contrasted with other studies showing an increased risk for coronary heart disease with low weight at birth and during infancy.20,23,24 Most of these studies, however, did not specifically test the association of coronary heart disease with patterns of weight gains but rather with body weight at one point in infancy, which depends both on previous weight and weight gain. In interpreting the results of the present study, it should be emphasized that in humans, the weight change from birth to age 8 days cannot be considered as a true "growth parameter." Weight changes during this period mainly reflect the amount of formula ingested, which in turn could be influenced by a number of factors, including minor illnesses, perinatal depression, or slow meconium passage. Also, weight changes during this period are likely influenced by the degree of reduction in total body water, which is affected by mild overhydration or underhydration at the time of delivery. If confirmed by others and if in part causal, the present findings may lead to short interventions in infants to prevent long-term development of obesity. Because the prevalence of obesity continues to increase worldwide and its prevention and treatment are frequently unsuccessful,1–5 new strategies based on a life-course approach may be useful to prevent obesity and related cardiovascular risk factors.
The present study confirms the previously reported associations of adult overweight status with weight gain in the first few months of life.17,18 The life-course plot (Figure 2), however, suggests that the first week of life may be particularly sensitive. The present study also confirms the association of adulthood overweight with birth weight,21,22 maternal overweight,46 and increasing age of the subject.1 Unlike what has been described in a nationally representative European American sample of the same age group, in the present sample, women were less likely to be overweight than men, and overweight was not associated with income.47 Some of the adjusted analyses, but not the unadjusted analysis, revealed an increased risk for overweight in individuals assigned to the soy-based compared with the cow milk–based formula (Tables 2 and 3). This incidental finding should be taken with caution because of the inconsistency in results between analytical models and the borderline level of statistical significance, but it suggests that soy-based formula should be further investigated as a possible risk factor for overweight.
The present study had some limitations. Early cardiovascular disease could not be assessed by telephone interview in this sample of relatively young adults. Therefore, the present data do not provide information on the cardiovascular consequences of the association between early infancy weight gain and adulthood obesity. Another limitation of the present study was the low prevalence of obesity and overweight. The prevalence of overweight was lower in this sample (32%) than in the general population of European Americans in this age range (55%) based on measured rather than self-reported weight and height,5 which suggests underreporting of overweight in the present sample. Because it is unlikely that the presence or magnitude of underreporting was associated with absolute weight gain during the first week of life, this limitation likely resulted in a nondifferential misclassification, thus resulting in a bias toward the null hypothesis and an underestimation of the true effect size. Alternatively, the low prevalence of overweight and obesity in this sample reflects the relatively high socioeconomic status of the study subjects,37 because the source population included many infants born to students and young faculty at the University of Iowa. The relatively small number of subjects classified as obese (BMI 30 kg/m2) was insufficient to perform meaningful analyses, and the analyses are reported with overweight status (BMI 25 kg/m2) as the outcome. Although not statistically significant, the direction of the associations was similar with the small number of obese subjects (data not shown). Birth weight was reported by the mother, but a significant reporting error is unlikely because it was assessed only 8 days after delivery. Should such reporting error have occurred, it would be unlikely to be associated with the outcome, which took place several decades later. Therefore, such bias would also have led to an underestimation of the effect size. Introduction of complementary foods after 28 days of life may have confounded the association of adult overweight with weight gain during the first 112 days of life but not with weight gain in the first week of life. The use of z scores obtained from smoothed cross-sectional reference data to model longitudinal data are controversial and has its limitations. These limitations, in the models that used z scores, may explain in part the large differences in ORs between the unadjusted and adjusted analyses and why, in the unadjusted analysis, the association of change in z score with adult overweight was not significant; however, after adjustment for important confounding factors, the results with absolute value of weight change or z scores were similar. Because of the characteristics of the sample, the present findings cannot be generalized to non-European American individuals or to breastfed infants, and our conclusions only apply to formula-fed infants. The relatively low rate of complete data (72%) was also of concern but is not unusual for a birth cohort with follow-up over 3 decades.
The study also had unique strengths. We used a life-course plot to identify potentially sensitive or critical periods of weight gain for the development of obesity40 rather than arbitrarily chosen periods. By plotting the standardized ;-coefficients of a multiple logistic regression that included several WAZ values measured during infancy, adjusted for each other and for important confounding variables, this method is the first, to the best of our knowledge, to allow identification, based on data, of potentially critical periods of weight gain for adult outcomes. One of the limitations of this method is the possibility that the addition of an observation between 2 observations may modify the observed slope and therefore the interpretation of the plot. Consequently, to provide useful information, this method assumes that measurements are close to one another, as described in detail by Cole.40 In the present study, this assumption was met, and therefore this limitation is unlikely to have played an important role. Compared with breastfeeding, formula feeding has been associated with more rapid absolute weight gain in early infancy30,31 and with obesity in adolescence,32,33 but because the present study was limited to exclusively formula-fed subjects, our finding cannot be explained by infant feeding mode. Additionally, all infant measurements other than birth weight were performed prospectively as part of a rigorous research protocol.
In conclusion, the present study demonstrates a significant increase in the risk of overweight status in adulthood associated with increasing weight gain during the first week of life. This finding may have important research and public health implications at a time when obesity prevention is becoming a global public health priority to reduce cardiovascular and other obesity-related diseases.
Acknowledgments
Data collection for this study was originally funded by National Institutes of Health (NIH) contract N01-HD-8-3279 and a grant from the Infant Formula Council (now the International Formula Council). Dr Stettler is funded in part by NIH grant K23-RR-016073. The authors are thankful to the study subjects, their families, and the staff of the Fomon Infant Nutrition Unit at the University of Iowa, the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania, and The Children’s Hospital of Philadelphia.
Disclosure
The Fomon Infant Nutrition Unit receives research grants from and conducts clinical trials funded by Ross Product Division, Nestle, and Mead Johnson Nutritional. Dr Ziegler has received honoraria for speaking from the same companies, mostly in continuing education settings. In the past, Dr Stallings received an unrestricted educational and research grant from Bristol Myers Squibb for The Children’s Hospital of Philadelphia Nutrition Center.
Footnotes
Presented in part at the 3rd Conference of Epidemiological Longitudinal Studies in Europe, Bristol, United Kingdom, September 22–24, 2004, and at the North American Association for the Study of Obesity, Las Vegas, Nev, November 14–18, 2004.
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