Crossing Growth Percentiles in Infancy and Risk of Obesity in Childhood FREE

The obesity epidemic has spared no age group, including young children.^1- 2 Recent evidence suggests that even infants experienced a dramatic rise in excess weight in the past 20 years,² and that already by 3 years of age obese children have elevated levels of inflammatory markers linked to heart disease later in life.³ Epidemiologic studies^4- 7 have also shown that excess weight gain in the first half of infancy predicts later obesity and higher blood pressure. These data imply thatcontributors to the epidemic can be found as early as infancy and suggest that identification of children in the earliest stages of life who are at highest risk is potentially crucial to stemming the rising tide of obesity.^2,8- 9 One limitation of these previous studies is the variety of metrics used to characterize weight gain during infancy. There is a need for potentially practical clinical tools to identify infants at highest risk.

During well-child visits,¹⁰ clinicians routinely use the Centers for Disease Control and Prevention (CDC) growth charts to document serial measures of weight and length and to screen for abnormalities in weight status. The CDC growth charts include predefined major percentile lines to highlight the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles for age and sex.¹¹ In toddlers and school-age children, clinicians often use upward crossing of 2 major percentile lines in weight-for-length or body mass index (calculated as weight in kilograms divided by height in meters squared) to identify children at risk of developing obesity. Mei et al¹² found that crossing weight-for-length percentiles during the first 2 years of life is more common than at older ages. Given the high rate of shifting in weight-for-length, they concluded that upward crossing of weight-for-length percentiles in infancy is not of concern. To our knowledge, however, no previous studies have examined whether crossing major percentiles in the CDC growth charts during the first 24 months of life is associated with later obesity.

The purpose of this longitudinal study was to examine associations of upward crossing of major percentiles in weight-for-length in the first 24 months of life with the prevalence of obesity at ages 5 and 10 years.

We culled longitudinal data from a clinical database of 1 649 123 well-child visits by 244 562 children. The study population consisted of children younger than 11 years of age who were seen for well-child visits at any of the 14 health centers of Harvard Vanguard Medical Associates/Atrius Health in eastern Massachusetts from January 1, 1980, through December 31, 2008. Throughout the study period, Harvard Vanguard Medical Associates used a completely electronic medical record system that contained demographic and growth data. Details of the data collection methods have been previously published.^2,13

To be included in the analyses, children needed at least 2 measurements within at least 1 of four 6-month intervals in the first 24 months of life, from which we could calculate the number of weight-for-length percentiles they crossed. Of the 244 562 children, 100 447 had at least 2 measurements within 1 of these 6-month intervals. Of these 100 447 children, 44 622 had either 5- or 10-year anthropometric outcomes. The sample size for our final analyses included these 44 622 children with 122 214 weight-for-length measures between the ages of 1 and 24 months and height/weight measurements at 5 or 10 years. An individual child could contribute to each of the four 6-month intervals. Of note, because birth weight and especially length were not universally recorded in the outpatient electronic medical record, we could not use birth as a starting age. Instead, we used a well-child visit anytime in the first month of life, and we called this time point “1 month.” The study protocol was approved by the institutional review board of Harvard Pilgrim Health Care.

Medical assistants at Harvard Vanguard Medical Associates health centers measured length or height and weight according to the written standardized protocol of the health centers. Weight was measured to the nearest 0.25 lb on a calibrated pediatric scale. Using a paper-and-pencil technique, medical assistants measured recumbent length in children younger than 24 months. In this technique, the child lies supine on a piece of paper atop an examination table with his or her face looking at the ceiling. The medical assistant draws a tick mark abutting the top of the child's head. The medical assistant then straightens the child's legs, flattens the child's knees, flexes the child's foot to 90°, and marks the paper at the bottom of the child's heels. The medical assistant measures and records the distance between the marks, to the nearest quarter-inch, with a flexible tape. For children aged 5 and 10 years, they measured height standing, without shoes.

In a validation study¹⁴ among children aged birth to 24 months conducted at one of the participating Harvard Vanguard Medical Associates health centers, the paper-and-pencil method systematically overestimated children's length compared with a reference method (recumbent length measuring board). This bias did not depend meaningfully on the age or sex of the child. Thus, as previously described,¹⁵ we used a regression correction factor to adjust for this systematic overestimation: [(0.953 × length measured by paper-and-pencil method) + 1.8 cm].

Our main exposure was the number of major weight-for-length percentile lines crossed during each of the four 6-month intervals from 1 to 24 months of age. To estimate this value, we first chose weight and length measurements for each child that were closest to each starting time point, that is, 1 month, 6 months, 12 months, 18 months, and 24 months. We allowed 30 days more or less from the 1-, 6-, 12-, 18-, and 24-month visits. A child's measurements could contribute to more than 1 interval. For example, measurements from the 6-month visit would be used as the ending measurements for the 1-to-6-month age interval and as the starting measurement for the next age interval, 6 to 12 months. We then used the CDC 2000 growth charts¹¹ to assign an age- and sex-specific weight-for-length percentile to each child's measurement. We calculated the number of major percentile lines that the child crossed during each of four 6-month intervals (ie, 1-6 months, 6-12 months, 12-18 months, and 18-24 months). We used the CDC's predefined major percentile lines to highlight the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles because these are the cut-points printed on the CDC growth charts and are commonly used by clinicians to track growth in primary care. For example, if a child's weight-for-length percentiles at ages 6 months and 12 months were 14th and 45th, respectively, then he or she crossed upwards 1 major percentile (the 25th) in weight-for-length in that 6-month interval. If another child's weight-for-length percentiles at ages 6 and 12 months were 94th and 55th, respectively, then he or she crossed downwards 2 major percentiles (the 90th and 75th) in weight-for-length in the 6-month interval. Details of the sample sizes in each interval are presented in Table 1.

In secondary analyses, we also examined ever crossing upwards 2 or more weight-for-length percentiles during any of the 4 intervals. For the secondary analyses, we included 17 322 participants with 86 610 weight-for-length measurements during all four 6-month intervals and outcome data at ages 5 or 10 years and complete covariate information.

From heights and weights at ages 5 and 10 years, we calculated body mass index. Our main outcome at ages 5 and 10 years was prevalence of obesity, defined as an age- and sex-specific body mass index at the 95th percentile or higher.¹⁶

From enrollment records, we extracted information on each child's date of birth, sex, visit dates, and race/ethnicity. Parental or clinician report of child's race/ethnicity was documented in the record using the categories white, black, Hispanic, American Indian/Alaska Native, Asian, and other. Race/ethnicity was missing for 10 206 participants (22.9%). Comparison of them with the 34 416 participants with nonmissing race/ethnicity data showed that the 2 groups did not differ by number of percentiles crossed upwards: 64% of children with nonmissing race/ethnicity data vs 65% of children with missing race/ethnicity data crossed upwards 2 or more weight-for-length percentiles in any of the four 6-month intervals in the first 24 months of life.

In the primary analyses of crossing percentiles within each 6-month interval, we ran the observed prevalence of obesity at ages 5 and 10 years. We stratified the analyses according to starting weight-for-length percentile (ie, <25th, 25th-50th, 50th-75th, and 75th-90th) and excluded children whose weight-for-length percentile was higher than the 90th percentile at the beginning of each 6-month interval because they could not cross upwards 2 major percentile lines during that interval. We used generalized linear mixed models (PROC GLIMMIX in SAS, version 9.2; SAS Institute, Inc, Cary, North Carolina) to test differences in the observed prevalence of obesity at ages 5 and 10 years associated with crossing upwards 2 or more major weight-for-length percentile lines in the first 6 months of life compared with crossing upwards 2 or more major weight-for-length percentiles at any other period (ie, 6-12 months, 12-18 months, and 18-24 months). All models used random effects to account for individuals who contributed at least 1 observation.

In analyses of ever crossing upwards 2 or more major weight-for-length percentiles, we used SAS Proc MI (SAS Institute, Inc) to impute 10 values for missing race/ethnicity. After imputation, the data were combined and all analyses were performed using Proc MI ANALYZE (SAS Institute, Inc). In multivariable logistic regression, we adjusted for child's sex, year of outcome measurement, exact age at outcome measurement, and race/ethnicity to examine the odds of obesity (body mass index at the 95th percentile or higher vs at less than the 95th percentile) at ages 5 and 10 years. We report odds ratios and 95% CIs. All models were fit separately for boys and girls; we combined results and adjusted for sex because sex-specific estimates were similar. We conducted all analyses using SAS, version 9.2 (SAS Institute, Inc).

Table 2 shows the sex, race/ethnicity, and obesity prevalence among the 44 622 participating children, and Table 3 summarizes the number of children who crossed less than 0 (ie, moved downward across major percentiles), 0, 1, and 2 or more percentiles. Obesity prevalence was 11.6% at age 5 and 16.1% at age 10 years. In the first 6 months of life, 43% of participants crossed upwards 2 or more weight-for-length percentiles. Fewer children crossed upwards 2 or more weight-for-length percentiles after 6 months of age: 20% from 6 to 12 months, 14% from 12 to 18 months, and 11% from 18 to 24 months (Table 3). We observed similar crossing patterns for boys and girls (Table 3).

Table 4 shows the observed prevalence of obesity at ages 5 and 10 years according to the number of percentile lines crossed in each of the four 6-month intervals, stratified by starting weight-for-length percentile. As expected, starting at a higher percentile at any time between 1 and 24 months was associated with higher obesity prevalence at 5 or 10 years than starting at a lower percentile (Table 4). For example, a 6-month-old child starting at the 75th to 90th percentile who crossed upwards 2 or more percentiles in the next 6 months had an observed obesity prevalence of 29.7% at age 5 years, much higher than the 7.4% in a 6-month-old child who instead started at less than the 25th percentile.

Crossing upwards 2 or more percentiles in the first 6 months of life was associated with a high prevalence of obesity at ages 5 and 10 years. For example, at age 5, the prevalence was 32.9% for 1-month-old infants whose weight-for-length started at the 75th to 90th percentile and crossed 2 or more percentiles by age 6 months. This prevalence was higher, compared with the prevalence of 29.7% for those crossing between 6 and 12 months of age, 32.0% for 12 to 18 months, and 31.8% for 18 to 24 months (Table 4). At age 10 years, we also observed a high prevalence of obesity in children with upward crossing of 2 or more percentiles in the first 6 months of life and who were in the 75th to 90th percentile at baseline (34.6%) (Table 4 and Figure).

In secondary analyses, we found that 11 090 (64.4%) of 17 233 children had ever crossed upwards 2 or more percentiles in the first 24 months of life. In covariate-adjusted regression analyses, we found elevated odds of obesity at ages 5 years (odds ratio, 2.08; 95% CI, 1.84-2.34) and 10 years (1.75; 1.53-2.00) among children who had ever crossed upwards 2 or more major weight-for-length percentiles in the first 24 months of life vs those who had crossed less than 2 major weight-for-length percentiles in the first 24 months of life (Table 5).

In this study of more than 40 000 children with more than 120 000 weight-for-length measurements between the ages of 1 and 24 months, we found that crossing upwards 2 or more weight-for-length percentiles in the first 24 months of life was associated with elevated odds of obesity at ages 5 and 10 years compared with children who crossed fewer than 2 major weight-for-length percentiles. Upward crossing of 2 or more major weight-for-length percentiles in the first 6 months of life not only was common but also was associated with high risks of obesity 5 and 10 years later.

In 2004, Mei et al¹² reported that crossing growth percentiles from 0 to 24 months of age was common among 10 844 participants in the California Child Health and Development Study. In the first 6 months of life, 62% of children crossed 2 major weight-for-length percentiles either upward or downward. The authors concluded that because of the high rate of shifting in weight-for-length during infancy, concern about overweight in infancy was unnecessary. Similar to Mei et al, we found high rates of crossing of major weight-for-length percentiles in the first 6 months of life. However, we found that crossing of weight-for-length in the first 6 months of life was of consequence. Upward crossing of at least 2 percentile lines from 1 to 6 months predicted a prevalence of obesity at ages 5 and 10 years that ranged from 11.5% to 34.6%. With few exceptions, these frequencies were higher, albeit not always significantly, than those associated with crossing during any of the other 6-month intervals. Within each interval, crossing at least 2 lines was associated with higher risks than crossing fewer lines. In addition, similar to a study predicting obesity at age 12 years from measures at 2 to 5 years of age,¹⁷ we observed that having ever crossed upwards 2 or more major weight-for-length percentiles in the first 24 months of life was associated with 2-fold higher odds of obesity at age 5 years and 75% higher odds at age 10 years.

Our findings extend a growing body of literature indicating that weight gain in the first few months of life contributes to the development of obesity.^18- 19 Previous studies of both contemporary^20- 21 and historical²² cohorts and 2 recent systematic reviews^4- 5 of infant growth and obesity have concluded that infants at the highest end of the weight or body mass index distribution, and infants who grew most rapidly (usually measured as weight gain), were more likely to be obese later in life. Many of these studies, however, have been limited by their relatively small sample sizes,²³ by lack of data among children younger than 24 months,¹⁷ or by reliance on weight measures alone without length measurements.^5,20- 22,24 Our large sample size of children with weight and length measures who were younger than 24 months allowed precise estimates within strata defined both by starting weight-for-length percentiles and number of percentile lines crossed.

One feature of our study lends itself to potential clinical application. Assessing how many percentiles a child crosses has more clinical utility and is more practical than calculating an epidemiologic exposure measure, such as change in weight-for-length z score, as many studies have done. Because pediatric clinicians routinely document serial measures of weight and length and screen for abnormalities in weight status using the published CDC growth charts, crossing percentiles could be used to assess early risk of obesity in pediatric primary care of infants younger than 24 months. Nevertheless, it remains to be seen whether interventions based on such early identification result in improvements in child health.

Even if crossing weight-for-length percentiles can serve as a tool for pediatric clinicians to identify excess gainers in infancy, there is still the need to identify modifiable determinants of excess gain in adiposity and what the proper response should be.⁸ A robust literature has emerged regarding prenatal and perinatal predictors of childhood adiposity,^6,25- 30 but few studies have examined whether these factors also predict weight gain in early infancy. Furthermore, there is a need to examine trade-offs of more rapid vs less rapid weight gain for different outcomes. At least among infants born preterm, more rapid weight gain in early infancy predicts better neurocognitive outcomes in childhood.^31- 32 Whether this same situation holds with term infants is less clear.³³ Thus, the amount of weight gain that optimizes both neurocognitive and obesity risk may differ by gestational age. Investigating these potential determinants of excess infant adiposity gain could lead to intervention strategies in clinical and public health settings to prevent childhood obesity and its consequences.

When interpreting our study, several limitations should be considered. First, the ambulatory care records we examined infrequently contained birth weight. Rather, we used weights and lengths in the first month of life. Thus, our estimates of crossing percentiles in the first 6 months of life do not reflect any shifts that may have occurred between birth and the first well-child care visit. Second, we used clinically measured lengths, which tend to overestimate actual length. To overcome this limitation, we used the regression estimate from our previous validation study to statistically correct for this systematic overestimation. Third, race/ethnicity was missing for approximately 20% of the children in this study, although we did not observe differences in rates of crossing percentiles among children with and without complete race/ethnicity data. Finally, all participants in this study had health insurance and access to primary care during the first 24 months of life (1-24 months) and during childhood (5- or 10-year visit). Our results may not be generalizable to more disadvantaged populations with less access to primary care.

Upward crossing of major weight-for-length percentiles in infancy, especially in the first 6 months of life, is associated with high rates of obesity at ages 5 and 10 years. These results raise the possibility of using this metric as a practical tool to identify children who may be at high risk of obesity in pediatric settings where clinicians already weigh, measure, and plot growth for infants at regular intervals. Our findings and those of the growing literature in this area support the need to identify modifiable determinants of excess gain in adiposity in infancy that can inform the design of clinical and public health interventions to modify these determinants.