In this study, we assess prenatal and postnatal antecedents of obesity at 10 years of age in a large cohort of children born EP.
Abstract
BACKGROUND:
Childhood obesity is a pervasive public health problem with risk factors such as maternal prepregnancy BMI and rapid infant weight gain. Although catch-up weight gain promotes more favorable neurodevelopment among infants born preterm, it is not clear whether faster weight gain early in life, or other correlates of preterm birth, are associated with later obesity in this population.
METHODS:
We used prospective data from the multicenter, observational Extremely Low Gestational Age Newborn Study. Among 1506 eligible individuals in the initial cohort, 1198 were eligible for follow-up at 10 years of age. We examined BMI in 871 children (58% of the cohort; 74% of survivors) and analyzed relationships between antecedents and overweight or obesity at 10 years of age. A time-oriented approach to multinomial multivariable regression enabled us to calculate odds of overweight and obesity associated with pre- and postnatal antecedents.
RESULTS:
Prepregnancy maternal BMI ≥25 and top quartile infant weight gain in the first year were associated with increased risk of both overweight and obesity at 10 years of age. Single marital status was a risk factor for later child obesity and exposure to tobacco smoke was a risk factor for later child overweight.
CONCLUSIONS:
The risk profiles for overweight and obesity at 10 years of age among children born extremely preterm appear to be similar to the risk profiles of overweight and obesity among children born at term.
What’s Known on This Subject:
Although extremely preterm (EP) infants typically exhibit early growth delay, these individuals are nonetheless at risk for childhood obesity. It is unclear what factors are associated with childhood obesity in this EP population.
What This Study Adds:
We found that a mother’s prepregnancy BMI and a child’s faster weight gain in the first and second years were associated with obesity at 10 years of age among EP infants.
Obesity is a pervasive public health problem in the United States that affects 17% of children and 35% of adults.1 The etiology of obesity is thought to be influenced by genetic and environmental factors, including maternal obesity and gestational weight gain, smoking during pregnancy, sleep, and rapid infant weight gain.2,3 Such environmental factors are presumed to operate early in the causal pathway to obesity, and, consequently, the emphasis has been on primary prevention and early recognition of risk factors, especially in the “first 1000 days” between conception and age 2.4–6
Although rapid weight gain in the first 2 years of life has been associated with increased risk of obesity, hypertension, and metabolic disease in children born at term and late preterm,3,7 it is not known if this association is relevant to children born before 34 weeks’ gestation.8 Infants with extremely low birth weight (ELBW) and born extremely preterm (EP) typically exhibit growth delay during their first postnatal months9 and then experience a gradual increase in weight z score during childhood and adolescence, a process referred to as “catch-up” growth.10–12 By 14 to 20 years of age, cohorts with ELBW attain a mean weight similar to that of controls with normal birth weight.10,12 In one of the few studies of weight gain among children born EP, BMI increased significantly more than term controls between 1 and 11 years of age, but BMI was similar to that of controls at 11 years of age.13 Notably, in one cohort of ELBW infants, 12% were obese at 8 years and 19% were obese at 14 years, an increase over time that reflects the ongoing obesity epidemic and mirrors the general pediatric population.11
Among neurologically normal infants with ELBW, predictors of BMI at 14 years of age include birth weight z score (positive correlation), race (higher among white individuals than African Americans), sex (higher among girls than boys), maternal BMI (positive correlation), and weight gain during infancy and childhood (positive correlation).12 Except for the length of initial hospitalization (higher BMI with longer hospitalization),14 few characteristics and exposures in the perinatal and postnatal periods have been associated with childhood BMI.11,14,15 No studies of growth in children who were born EP have included >250 children, and we are not aware of studies using a cohort born in the 21st century, an era in which the prevalence of overweight and obesity among US children has risen by 15%.16 Our aim was to identify perinatal, infancy, and early childhood antecedents of overweight and obesity at 10 years in a large cohort of infants who were born EP born in the midst of the obesity epidemic.
Methods
Participants
The Extremely Low Gestational Age Newborn (ELGAN) study is a multicenter prospective, observational study of infants who are born EP.17 A total of 1506 infants born before 28 weeks’ gestation were enrolled during the years 2002–2004. From this original cohort, 889 (59%) survived to 10 years of age and returned for follow-up. Of the 889 who returned, 871 (90%) had complete height and weight measurements. Enrollment and consent procedures for this follow-up study were approved by the institutional review boards of all participating institutions, and additional details related to study procedures have been published previously.17
Maternal Characteristics and Exposures
After delivery, a trained research nurse interviewed each mother in her native language using a structured data collection form. Shortly after the mother’s discharge, the research nurse reviewed the maternal chart using a second structured data collection form. The medical record was used for events after admission. The clinical circumstances that led to preterm delivery were operationally defined by using both data from the maternal interview and data abstracted from the medical record.18 We grouped maternal BMI into categories corresponding to US growth standards: <18.5 is underweight, 18.5 to 24.9 is healthy, 25.0 to 29.9 is overweight, 30.0 to 34.9 is obese, 35.0 to 39.9 is Class 2 obesity, and ≥40 is Class 3 obesity,19 and we further collapsed these to 3 groups, which were healthy weight (<25), overweight (25–29.9), and obese (≥30).
Perinatal and Neonatal Exposures
Procedures for placenta processing, microbiology, and histology are described in detail elsewhere.20,21 Gestational age estimates were based on a hierarchy of presumed validity. We regarded estimates based on dates of embryo retrieval, intrauterine insemination, or fetal ultrasound before the 14th week (62%) as most valid, followed by ultrasound at ≥14 weeks (29%), last menstrual period (7%), and, finally, gestational age recorded in NICU (1%). Mean blood pressure was measured either directly from an intra-arterial catheter or from an automated blood pressure cuff. A diagnosis of a tracheal colonization required the recovery of a pathogen from tracheal aspirate. Diagnoses of patent ductus arteriosus (PDA), pneumothorax, pulmonary interstitial emphysema, and pulmonary hemorrhage were those made by the clinicians caring for the ELGAN study neonates. The child’s necrotizing enterocolitis status was classified according to the modified Bell staging system.22 Retinopathy of prematurity was classified according to international guidelines.23 The diagnosis of bronchopulmonary dysplasia and/or chronic lung disease was based on whether the child was receiving supplemental oxygenation at 36 weeks postmenstrual age.
Growth and Outcomes
The birth weight z score is the number of SDs the infant’s birth weight is greater than or less than the median weight of infants at the same gestational age in referent samples not delivered for preeclampsia or fetal indications.24–26 Weight in kilograms was collected as part of the clinical assessment at 1- and 2-year visits, and rates of weight gain between birth and 1 year and between 1 and 2 years were calculated and divided into quartiles. BMI percentiles at 10 years were calculated on the basis of age- and sex-specific US growth standards and divided into the following 3 categories: healthy weight (<85%), overweight (85%–94%), and obese (≥95%).
Analyses
We first evaluated the relationship between antecedent exposures from pregnancy through early life and overweight and obesity at 10 years. To identify all potential antecedents of obesity in this cohort, we included a large number of variables in initial bivariate comparisons. We included those that had been potential confounders in ELGAN investigations at a threshold that would avoid an incomplete assessment of confounding of both the exposures and outcome of BMI.27 Then we constructed adjusted models to assess all significant associations between these antecedent exposures and overweight and obesity at 10 years. Among antecedent exposures, we considered maternal demographic characteristics, newborn characteristics at birth, early and late postnatal treatments and events, and changes in weight between birth, 1, and 2 years. We considered the antecedents, a priori, as occurring no more frequently among children with overweight or obesity than among children with a healthy weight. We use time-oriented risk models (TORMs) because antenatal antecedents can influence the likelihood of postnatal antecedents. TORMs are multinomial models fitted in stages or “epochs,” in which each epoch includes variables grouped by the chronological order in which they occur or are identified (eg, demographic and pregnancy [Table 1], perinatal [Table 2], neonatal [Tables 2 and 3], etc).28,29 Variables included in an epoch are entered into the model, and then the model is reduced so that only significant variables remain. The dropped variables are then added back singly to see if significance changes before moving to the next stage of variables. We selected variables as confounders if identified in the literature or if they were associated with both the exposure and the outcome with probabilities ≤0.25 to avoid inappropriate exclusion of confounding.27 We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for the multinomial outcomes overweight and obese (Tables 4 and 5). Children whose BMI percentile was <85 (healthy weight) comprised the referent category.
TABLE 1.
Selected Prenatal Characteristics and Maternal Demographics Associated With Offspring Overweight and Obesity at 10 Years
| Maternal Characteristic | BMI Percentile at 10 y | Row N | ||
|---|---|---|---|---|
| <85 | 85–94 | ≥95 | ||
| Racial identity | ||||
| White | 65 | 55 | 64 | 554 |
| African American | 25 | 27 | 28 | 223 |
| Other | 9 | 18 | 11 | 92 |
| Hispanic: Yes | 8 | 17 | 14 | 85 |
| Single marital status: Yes | 37 | 48 | 44 | 343 |
| Prepregnancy BMI | ||||
| <25 | 62 | 49 | 34 | 484 |
| 25 to <30 | 17 | 27 | 25 | 163 |
| ≥30 | 20 | 24 | 41 | 193 |
| Gestational diabetes: Yes | 3 | 3 | 5 | 26 |
| Passive smoke exposure: Yes | 23 | 22 | 36 | 207 |
| Conceived while using birth control: Yes | 14 | 19 | 9 | 121 |
| Aspirin used during pregnancy: Yes | 5 | 5 | 9 | 47 |
Percentage of each characteristic by BMI percentile category.
TABLE 2.
Selected Perinatal and Neonatal Characteristics Associated With Offspring Overweight and Obesity at 10 Years
| BMI Percentile at 10 y | Row N | |||
|---|---|---|---|---|
| <85 | 85–94 | ≥95 | ||
| Placenta characteristics | ||||
| Aerobe species isolated: Yes | 34 | 25 | 38 | 261 |
| Chorionic plate inflammationa: Yes | 18 | 13 | 30 | 152 |
| Chorion and/or decidua inflammationb: Yes | 34 | 32 | 47 | 282 |
| Fetal stem vessel infiltrationc: Yes | 24 | 15 | 36 | 200 |
| Umbilical cord vasculitis: Yes | 17 | 9 | 22 | 128 |
| Delivery characteristics | ||||
| Cesarean delivery: Yes | 67 | 71 | 55 | 576 |
| Duration of membrane rupture (h): <1 | 60 | 59 | 47 | 507 |
| Multiple-fetal gestation: Yes | 37 | 36 | 19 | 305 |
| Neonatal characteristics | ||||
| Lowest MAP lowest quartile: Yes | 21 | 15 | 26 | 176 |
| Lowest Pco2 lowest quartile: Yes | 21 | 19 | 29 | 157 |
| Definite tracheal colonization: Yes | 23 | 21 | 14 | 188 |
| Antibiotic, wk 1: Yes | 98 | 97 | 96 | 851 |
| Sedation in first mo: Yes | 29 | 20 | 26 | 242 |
| PDA: Yes | 69 | 72 | 61 | 596 |
| PDA treatment: Yes | 63 | 62 | 48 | 530 |
| Ventriculomegaly: Yes | 10 | 8 | 15 | 92 |
| ROP, plus disease: Yes | 10 | 8 | 16 | 92 |
| Pulmonary hemorrhage: Yes | 3 | 3 | 7 | 31 |
Percentage of each characteristic by BMI percentile category. MAP, mean arterial pressure; ROP, retinopathy of prematurity.
Stage 3 and severity 3.
Grades 3 and 4.
Grades 3, 4, and 5.
TABLE 3.
Selected Early Life Growth Measures Associated With Offspring Overweight and Obesity at 10 Years
| Characteristic | BMI Percentile at 10 y | Row N | ||
|---|---|---|---|---|
| <85 | 85–94 | ≥95 | ||
| Gestational age, wk | ||||
| 23–24 | 21 | 20 | 17 | 180 |
| 25–26 | 46 | 40 | 51 | 397 |
| 27 | 33 | 41 | 32 | 294 |
| Birth wt, g | ||||
| ≤750 | 40 | 31 | 24 | 322 |
| 751–1000 | 42 | 42 | 54 | 376 |
| >1000 | 19 | 26 | 22 | 173 |
| Birth wt z scorea | ||||
| <−2 | 7 | 4 | 4 | 53 |
| ≥−2 to <−1 | 14 | 10 | 7 | 112 |
| ≥−1 | 79 | 86 | 81 | 706 |
| Top quartile wt gain in y 1,b Yes | 20 | 40 | 40 | 199 |
| Top quartile wt gain in y 2,b Yes | 22 | 30 | 43 | 195 |
Percentage of each characteristic by BMI percentile category.
Yudkin et al24 standard.
Centers for Disease Control and Prevention standard.
TABLE 4.
ORs and 95% CIs for the Association of a BMI Percentile ≥95 at 10 Years
| Characteristic | Epoch 1, N = 838 | Epoch 2, N = 838 | Epoch 3, N = 833 | Epoch 4, N = 743 |
|---|---|---|---|---|
| Marital status: Single | 1.6 (1.0–2.5)a | 1.6 (1.0–2.6)a | 1.7 (1.1–2.8)a | 1.8 (1.1–3.1)a |
| Prepregnancy BMI ≥25: Yes | 1.6 (1.1–2.5)a | 1.7 (1.1–2.6)a | 1.8 (1.1–2.7)a | 1.8 (1.1–2.9)a |
| Passive smoking: Yes | 0.8 (0.5–1.4) | 0.8 (0.4–1.4) | 0.8 (0.4–1.4) | 1.0 (0.5–1.8) |
| Chorionic plate inflammation: Yes | 0.6 (0.3–1.1) | 0.5 (0.3–1.0) | 0.5 (0.3–1.0) | 0.6 (0.3–1.3) |
| Multiple-fetal gestation: Yes | — | 1.0 (0.6–1.6) | 0.9 (0.6–1.5) | 1.1 (0.6–1.9) |
| Birth wt z score: <−1 | — | 0.6 (0.3–1.1) | 0.6 (0.3–1.1) | 0.6 (0.3–1.3) |
| Definite tracheal infection | — | — | 1.0 (0.6–1.7) | 1.1 (0.6–1.9) |
| Sedation, d 1–28 | — | — | 0.6 (0.3–1.0) | 0.5 (0.3–0.9)b |
| Top quartile wt gain: Y 1 | — | — | — | 2.4 (1.5–3.9)a |
| Top quartile wt gain: Y 2 | — | — | — | 1.5 (0.9–2.5) |
Children in each percentile category are compared with the same referent group of children with a BMI <85. All models account for the correlations between children from the same pregnancy. Epoch 1 candidates include the following characteristics: race, single marital status, prepregnancy BMI ≥25, passive smoke exposure, got pregnant while using birth control, aerobic bacteria isolated from the placenta, inflammation of the chorionic plate, Cesarean delivery, and/or membranes ruptured >24 h. Epoch 2 candidates include the following characteristics: child’s sex, birth wt z score <−1, multiple-fetal gestation. Epoch 3 candidates include the following characteristics: lowest quartile for GA of lowest MAP in first 24 h, lowest quartile for GA on 2 of the first 3 postnatal days for Pao2, definite tracheal infection, conventional mechanical ventilation or high-frequency ventilation on d 7, and/or sedation in the first 28 d. Epoch 4 candidates include the following characteristics: top quartile wt gain from birth to 1 y, top quartile wt gain from 1 to 2 y, and/or 1 or both parents unemployed. GA, gestational age; MAP, mean arterial pressure; —, not applicable.
Denotes OR that is statistically significantly increased.
Denotes OR that is statistically significantly reduced.
TABLE 5.
ORs and 95% CIs for the Association of a BMI Percentile 85–94 at 10 Years With the Antecedents Listed on the Left
| Characteristic | Epoch 1, N = 838 | Epoch 2, N = 838 | Epoch 3, N = 833 | Epoch 4, N = 743 |
|---|---|---|---|---|
| Marital status: Single | 0.9 (0.5–1.4) | 0.8 (0.5–1.3) | 0.9 (0.5–1.5) | 0.9 (0.5–1.5) |
| Prepregnancy BMI ≥25: Yes | 3.1 (2.0–5.0)a | 3.2 (2.0–5.1)a | 3.4 (2.1–5.5)a | 4.0 (2.3–6.8)a |
| Passive smoking: Yes | 1.8 (1.1–3.0)a | 1.6 (1.0–2.7) | 1.6 (1.0–2.7) | 1.8 (1.0–3.2)a |
| Chorionic plate inflammation: Yes | 1.7 (1.0–3.0)a | 1.5 (0.9–2.5) | 1.5 (0.9–2.6) | 1.7 (0.9–3.0) |
| Multiple-fetal gestation: Yes | — | 0.5 (0.3–0.8) | 0.5(0.3–0.9) | 0.6 (0.3–1.2) |
| Birth wt z score: <−1 | — | 0.4 (0.2–0.8) | 0.4 (0.2–0.9) | 0.5 (0.2–1.0)b |
| Definite tracheal infection | — | — | 0.4 (0.2–0.8) | 0.4 (0.2–0.9)b |
| Sedation, d 1–28 | — | — | 0.9 (0.5–1.5) | 0.8 (0.5–1.5) |
| Top quartile wt gain: Y 1 | — | — | — | 2.1 (1.3–3.6)a |
| Top quartile wt gain: Y 2 | — | — | — | 2.5 (1.5–4.2)a |
Children in each percentile category are compared with the same referent group of children with a BMI <85. All models account for the correlations between children from the same pregnancy. Epoch 1 candidates include the following characteristics: race, single marital status, prepregnancy BMI ≥25, passive smoke exposure, got pregnant while using birth control, aerobic bacteria isolated from the placenta, inflammation of the chorionic plate, Cesarean delivery, and/or membranes ruptured >24 h. Epoch 2 candidates include the following characteristics: child’s sex, birth wt z score <−1, and/or multiple-fetal gestation. Epoch 3 candidates include the following characteristics: lowest quartile for GA of lowest MAP in first 24 h, lowest quartile for GA on 2 of the first 3 postnatal days for Pao2, definite tracheal infection, conventional mechanical ventilation or high-frequency ventilation on d 7, and/or sedation in the first 28 d. Epoch 4 candidates include the following characteristics: top quartile wt gain from birth to 1 y, top quartile wt gain from 1 to 2 y, and/or 1 or both parents unemployed. GA, gestational age; MAP, mean arterial pressure; —, not applicable.
Denotes OR that is statistically significantly increased.
Denotes OR that is statistically significantly reduced.
Results
Of the 871 children included in this analysis, 107 (12.2%) were classified as overweight and 103 (11.8%) as obese at 10 years. Children who had overweight or obesity at 10 years were more likely than others to have a mother who identified as a race other than white or African American, was <21 years of age at the time of enrollment, or was not married (Table 1). If the mother identified her ethnicity as Hispanic, her child had a 10% higher prevalence of overweight and a 5% higher prevalence of obesity at 10 years compared with non-Hispanic mothers. A maternal prepregnancy BMI of ≥30 and a diagnosis of gestational diabetes were also associated with higher percentages of obesity at 10 years. The children whose mothers reported passive (but not active) smoke exposure during pregnancy, conceived despite use of birth control, and consumed aspirin during pregnancy had the highest percentages of overweight or obesity at 10 years. Several placental, delivery, and neonatal characteristics were associated with obesity in bivariate comparisons (Table 2). We did not find any association between diagnoses of bronchopulmonary dysplasia and/or chronic lung disease, necrotizing enterocolitis, cerebral palsy, gross motor dysfunction, or neurodevelopmental impairments and overweight or obesity at 10 years (data not shown).
Although higher gestational age was not associated with increased risk of obesity or overweight at 10 years, the prevalence of obesity was prominently increased among singleton infants and infants with higher absolute birth weight and birth weight z scores (Table 3). Fifteen percent of singleton born infants were obese at 10 years compared with 7% of infants of a multiple gestation. Infants born weighing 751 to 1000 g and those weighing >1000 g at birth had 15% and 13% obesity prevalence at 10 years, respectively, compared with 7% among those born weighing ≤750 g. Infants born with a weight z score ≥−1 according to the Yudkin et al24 standard had an obesity prevalence of 13% compared with 8% and 6% of infants with a weight z score of <−2 and ≥−2 to <−1, respectively. Thirty eight percent of infants with weight gain in the top quartile during the first year of life were either overweight or obese at 10 years of age compared with a 19% prevalence among slower growing infants. Twenty one percent of infants with top quartile weight gain in the second year of life had obesity at 10 years compared with 9% of infants in the lower 3 quartiles.
In the final TORM for obesity, only single marital status (OR 1.8; 95% CI: 1.1–3.1), prepregnancy overweight (OR 1.8; 95% CI: 1.1–2.9), and weight gain in top quartiles in the first year of life (OR 2.4; 95% CI: 1.5–3.9) were associated with increased risk, and receipt of sedation in the first 4 postnatal weeks was associated with a decreased risk (OR 0.5; 95% CI: 0.3–0.9) (Tables 4 and 5). In the final TORM for overweight at age 10 years, prepregnancy overweight (OR 4.0; 95% CI: 2.3–6.8), maternal exposure to passive smoking (OR 1.8; 95% CI: 1.0–3.2), and weight gain in the top quartile in both the first (OR 2.1; 95% CI: 1.3–3.6) and second (OR 2.5; 95% CI: 1.5–4.2) years of life were associated with increased risk of overweight, whereas a birth weight z score <−1, and tracheal colonization were associated with a decreased risk. Given the TORM method, many variables did not reach significance and were dropped during model refinement. We repeated the epoch 4 model with imputed values for the missing year 1 and year 2 weight gain quartiles, but the ORs and CIs were essentially identical (data not shown). These variables are listed in the footnotes for Tables 4 and 5.
Discussion
We found that high maternal prepregnancy BMI was associated with high offspring BMI. In addition, socioeconomic indicators (mother’s marital status and passive smoke exposure) and infants’ weight gain in the first and second year were also associated with a higher likelihood of overweight and/or obesity at age 10 years. A decreased risk of overweight and obesity was found among children who were the product of a multiple gestation pregnancy or had a low birth weight z score.
Several of these risk factors have been described previously in studies of infants not selected on the basis of gestational age. Higher maternal prepregnancy BMI is a consistently described risk factor for subsequent offspring obesity across all populations of infants and children.6 Similarly, maternal tobacco use has been reported as a risk factor for increased offspring adiposity in many studies.6 However, in our cohort, although secondhand smoke exposure was a risk factor for obesity, active maternal smoking was not. This might be due to social desirability bias30 of answering a question about a widely known risk factor for prematurity and low birth weight among a population of mothers having just delivered their infant at an extremely low gestational age. It is also possible that these mothers would be more likely to report exposure to secondhand smoke rather than their own use. This, too, could be a manifestation of the social desirability bias. Our findings of maternal BMI and weight changes associated with subsequent weight status are similar to another cohort of ELBW infants.12
The prevalence of overweight and obesity in our sample was lower than nationally representative samples of a general population of US children ages 6 to 11 years.1 Multiple gestation births and a birth weight z score of <−1, factors that we found associated with decreased odds of obesity, were highly prevalent in our cohort, with 35% of infants being the product of a multiple gestation pregnancy and 19% with a birth weight z score of −1 or less. The 1 study of multiple gestations that we could find revealed no significant relationship between maternal BMI and childhood obesity. Twin or higher order multiple gestations occurred in 13% to 24% of ELBW populations,12,31 and our relatively higher number of multiple gestations may explain a lower prevalence of obesity at 10 years.
Among the other factors associated with decreased risk of overweight, but not obesity, at 10 years are having a birth weight z score of <−1 and having a tracheal colonization while in the NICU. On the other hand, exposure to sedation in the first 28 days of life was associated with decreased risk of obesity, but not of overweight status, at 10 years. How these factors might attenuate obesity risk is not readily apparent. One possibility is that active respiratory infections might be related to differences in energy use during this early postnatal period with potential changes in metabolic programming that result in lower adiposity later in childhood. Inflammation has been associated with obesity, and increased levels of neonatal systemic inflammation have been reported to precede the onset of obesity.32–34
Our finding that more rapid weight gain in the first 2 years of life was associated with overweight or obesity at 10 years has implications for those who provide posthospitalization care for individuals born EP. Although catch-up growth among infants born preterm appears to optimize neurodevelopment,35 the authors of multiple observational studies confirm that faster early postnatal growth (and particularly growth of weight out of proportion to length36) leads to higher adiposity and metabolic risk.37–39 Communicating healthy growth with parents is important because parents of children born preterm are more likely to perceive their healthy weight child as underweight40 and may see their overweight child as being a healthy weight. Efforts to standardize the most effective methods of measuring growth velocity should be encouraged.41
Our study has several limitations. The death of 308 individuals between enrollment and the evaluation of obesity at 10 years could introduce bias if factors associated with death modify the association between antecedents and obesity risk. The strongest predictor of mortality in our cohort was gestational age, and this mortality rate is similar to that reported in other cohorts of infants born EP.42 We know of no research among children born at 23 to 27 weeks’ gestation that suggests the strength of association is modified by gestational age. Among other reasons for loss of follow-up were inadequate biomarker data (related to the parent study’s primary outcome) and inability to contact the families. Children without biomarker data may have been healthier than the overall cohort, and those unable to be contacted were more likely to be from socioeconomically disadvantaged families. Considering mortality and reasons for incomplete data, we know of no research indicating these characteristics lead to systematic bias in antecedents or our outcomes. Accordingly, any comments we could make about selection bias in our sample would be speculative. BMI is not a perfect surrogate of ultimate health risk, and the reference population used to construct growth charts, although nationally representative, might not be appropriate for a cohort of children born EP or ELBW. A small percentage (4%) of the sample had a BMI <5 percentile, and these children were analyzed in the “healthy” weight category. Several potential covariates in our sample (eg, Hispanic ethnicity) had occurred infrequently and were collinear with other demographic factors, which limited their ability to be included in a parsimonious model. Strengths of this study include the sample size and prospective design that included a wide array of exposures. We recognize the delicate balance between statistical significance and magnitude of effects, especially in an exploratory study. We considered adjusting for multiple statistical comparisons, but because this analysis is predominantly exploratory, we chose a more inclusive view of potential antecedents of obesity in this extremely premature sample to provide a foundation for future confirmatory analyses.43 Although a number of pre-, peri-, and postnatal factors were identified in bivariate comparisons as described in our results, many of these factors have not been directly examined as antecedents of obesity in preterm populations and should be interpreted with caution.
Conclusions
In a cohort of children born at extremely low gestational age, the risk of overweight and obesity at 10 years is higher among those born to a mother with overweight or obesity and among those who gained weight more rapidly during the first 2 years. Our findings suggest continued attention be paid to rapid growth in the first years of life, even in this particularly vulnerable population of children.
Acknowledgments
We acknowledge the contributions of their subjects, and their subjects’ families, as well as site study coordinators listed below.
Baystate Medical Center, Springfield, Massachusetts: Karen Christianson, RN; Deborah Klein, BSM, RN.
Boston Children’s Hospital, Boston, Massachusetts: Maureen Pimental, BA; Collen Hallisey, BA; Taryn Coster, BA.
Tufts Medical Center, Boston, Massachusetts: Ellen Nylen, RN; Emily Neger, MA; Kathryn Mattern, BA.
University of Massachusetts Medical School, Worcester, Massachusetts: Lauren Venuti, BA; Beth Powers, RN; Ann Foley, EdM.
Yale University School of Medicine, New Haven, Connecticut: Joanne Williams, RN; Elaine Romano, APRN.
Wake Forest University, Winston-Salem, North Carolina: Debbie Hiatt, BSN (deceased); Nancy Peters, RN; Patricia Brown, RN; Emily Ansusinha, BA.
University of North Carolina, Chapel Hill, North Carolina: Gennie Bose, RN; Janice Wereszczak, MSN; Janice Bernhardt, MS, RN.
East Carolina University, Greenville, North Carolina: Joan Adams (deceased); Donna Wilson, BA, BSW; Nancy Darden-Saad, BS, RN.
Helen DeVos Children’s Hospital, Grand Rapids, Michigan: Dinah Sutton, RN; Julie Rathbun, BSW, BSN.
Sparrow Hospital, East Lansing, Michigan: Karen Miras, RN, BSN; Deborah Weiland, MSN.
University of Chicago Medical Center, Chicago, Illinois: Grace Yoon, RN; Rugile Ramoskaite, BA; Suzanne Wiggins, MA; Krissy Washington, MA; Ryan Martin, Massachusetts; Barbara Prendergast, BSN, RN.
William Beaumont Hospital, Royal Oak, Michigan: Beth Kring, RN.
Glossary
- CI
confidence interval
- ELBW
extremely low birth weight
- ELGAN
Extremely Low Gestational Age Newborn
- EP
extremely preterm
- OR
odds ratio
- PDA
patent ductus arteriosus
- TORM
time-oriented risk model
Footnotes
Dr Wood conceptualized this study, drafted the initial manuscript, and participated in revisions; Dr Linthavong conceptualized this study, drafted portions of the initial manuscript, and participated in revisions; Dr Perrin helped conceptualize this study and critically reviewed the analysis plan and manuscript; Dr Leviton conceptualized and designed the parent study and critically reviewed the analysis plan and manuscript; Ms Allred conceptualized and designed the parent study, performed all data analyses, and participated in revisions; Drs Kuban and O’Shea conceptualized and designed the parent study, participated in revisions, and critically reviewed the analysis plan and manuscript; and all authors approved the manuscript as submitted.
A complete list of nonauthor contributors appears in the Supplemental Information.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Funded by National Institutes of Health and National Institute of Neurological Disorders and Stroke grants 5U01NS040069-05, 2R01NS040069-09, and 1UG3OD023348-01. Funded by the National Institutes of Health (NIH).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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