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American Journal of Epidemiology Advance Access originally published online on December 8, 2008
American Journal of Epidemiology 2009 169(2):214-218; doi:10.1093/aje/kwn341
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American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Influence of Birth Weight on White Blood Cell Count in Biracial (Black-White) Children, Adolescents, and Young Adults

The Bogalusa Heart Study

Wei Chen, Sathanur R. Srinivasan and Gerald S. Berenson

Correspondence to Dr. Gerald S. Berenson, 1440 Canal Street, Room 1829, New Orleans, LA 70112 (e-mail: berenson{at}tulane.edu).

Received for publication July 7, 2008. Accepted for publication September 23, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The effect of birth weight on white blood cell (WBC) count among blacks and whites was examined in 2,080 children (aged 4–11 years, 57.4% white, and 49.2% male), 892 adolescents (aged 12–17 years, 57.2% white, and 50.8% male), and 1,872 adults (aged 18–38 years, 68.4% white, and 41.9% male) from Bogalusa, Louisiana, in 2005. After adjustment for age, sex, race, body mass index, and smoking status (in adolescents and adults), the WBC count decreased across quartiles of increasing birth weight specific for race, sex, and gestational age in children (Ptrend = 0.0007) and adults (Ptrend = 0.005). In multivariate regression analyses that included the covariates above, birth weight was inversely associated with WBC count in children (β coefficients (unit, cells/µL per kg) = –256, –241, and –251 for whites, blacks, and the combined sample, with P = 0.003, 0.029, and <0.001, respectively) and in adults (β = –224 and –211 for whites and the combined sample, with P = 0.015 and 0.008, respectively). These results show that low birth weight is associated with increased systemic inflammation as depicted by the WBC count in childhood and adulthood, thereby potentially linking fetal growth retardation to cardiovascular disease and diabetes.

birth weight; inflammation; leukocyte count

Abbreviations: WBC, white blood cell


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The growth of a fetus in an undernourished intrauterine environment is thought to result in adaptive fetal programming or metabolic imprinting with pathophysiologic consequences later in life (1, 2). Studies worldwide have linked low birth weight for gestational age, an indicator of intrauterine growth restriction, to increased risk of metabolic syndrome and its components, cardiovascular disease and type 2 diabetes (3, 4), disorders that all share inflammation as a common pathobiologic trait (5–8). Systemic low-grade inflammation has emerged as a strong independent risk factor for cardiovascular disease and type 2 diabetes (9–14). Further, a few studies have demonstrated an inverse association between birth weight and biomarkers of systemic inflammation in newborns and adults (15–17).

Epidemiologic and clinical studies have shown that the white blood cell (WBC) count, a widely available biomarker of systemic inflammation, is an independent predictor of cardiovascular disease (9–11, 18). Moreover, the WBC count is related to metabolic syndrome and its components (12, 19). However, information is scant at a community level in the general population regarding the effect of low birth weight on the WBC count among blacks and whites at different ages and growth periods. The present analysis examines this aspect as part of the Bogalusa Heart Study, a biracial (black-white) community-based investigation of the natural history of cardiovascular disease beginning in childhood (20).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study cohort
In the community (65% white, 35% black) of Bogalusa, Louisiana, a cross-sectional survey of 3,262 children and adolescents aged 4–17 years was conducted in 1992–1993; a survey of 2,571 young adults aged 18–38 years was conducted in 1995–1996. Birth weight records of the participants were obtained in 2005 from the Louisiana State Public Health Office. Exclusion of those with missing data on birth weight (n = 428) or gestational age (n = 687) or with a WBC count outside the clinically normal range (2,000–12,000/µL) (n = 22) resulted in 2,080 children (aged 4–11 years, 57.4% white, and 49.2% male), 892 adolescents (aged 12–17 years, 57.2% white, and 50.8% male), and 1,872 adults (aged 18–38 years, 68.4% white, and 41.9% male). Compared with individuals who were not included in the analyses, children and adults in this study sample showed no significant differences in age, race, sex, body mass index, and smoking status, except that 2,972 children were 0.2 year younger (P = 0.042).

All subjects in this study gave informed consent at each examination. For those under 18 years of age, consent of a parent/guardian was obtained. Study protocols were approved by the Institutional Review Board of the Tulane University Health Sciences Center.

Measurements
Examinations of children and adults followed the same protocols. Height and weight were measured twice to ±0.1 cm and to ±0.1 kg, respectively. Body mass index (weight (kg)/height (m)2) was used as a measure of overall adiposity. Information on cigarette smoking status was obtained from adolescents (12–17 years of age) and adults (18–38 years of age) as part of health habit questionnaires.

Whole blood was drawn by antecubital venipuncture into a tube containing ethylenediaminetetraacetic acid as an anticoagulant. The specimens were sent in cold-pack containers to the local Bogalusa Charity Hospital clinical laboratory. The laboratory determined triplicate WBC counts on the same day by using a Coulter Counter (Beckman Coulter, Inc., Miami, Florida) method and reported the average values later.

Statistical methods
Analysis of covariance was performed by using general linear models to test differences in continuous study variables between races. The differences in categorical variables were tested by a chi-square test. The relation between the WBC count and birth weight was examined by linear regression models, adjusting for age, sex, body mass index, race (for the combined sample), and smoking (for adolescents and adults). Because of a strong association between gestational age and birth weight, birth weight was adjusted to the mean values of gestational age in each race-sex group by regression analysis models. However, the mean values of unadjusted birth weight were given in Table 1 for description. For categorical analyses, quartiles of gestational age-adjusted birth weight were defined by using cutoff points in race-sex groups. Covariates-adjusted mean values of WBCs were calculated by general linear models and used for trend analysis by quartiles of birth weight. Statistical analyses were performed with SAS, version 9.0, software (SAS Institute, Inc., Cary, North Carolina).


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  		Table 1. White Blood Cell Count, Birth Weight, and Other Study Variables in Children, Adolescents, and Young Adults by Race, the Bogalusa Heart Study, 2005

 

   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Table 1 shows the mean values of the WBC count, unadjusted birth weight, and other study variables in children, adolescents, and adults by race. Significant racial differences (whites > blacks) were noted for gestational age, birth weight, and the WBC count in all 3 age groups; for the prevalence of smoking in adolescents and adults; and for body mass index (whites < blacks) in adults. Of note, the WBC count of adolescents was significantly lower (P < 0.001) than those of children and adults for both races, adjusting for sex and body mass index.

Figure 1 illustrates the relation of covariates-adjusted mean values of the WBC count to race- and sex-specific quintiles of gestational age-adjusted birth weight by age periods. The covariates included age, sex, race (total sample), body mass index, and smoking status (adolescents and adults). The WBC count significantly decreased with increasing quartiles of birth weight in white children (Ptrend = 0.031), black children (Ptrend = 0.006), and the combined sample of children (Ptrend = 0.0007). A similar significant trend was noted in white adults (Ptrend = 0.016), black adults (Ptrend = 0.059), and the combined sample of adults (Ptrend = 0.005). Adolescents showed a similar but nonsignificant trend in whites (Ptrend = 0.061) and the total sample (Ptrend = 0.240).


Figure 1
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  		Figure 1. Covariates-adjusted mean values of white blood cell (WBC) count by race- and sex-specific quartiles of gestational age-adjusted birth weight, the Bogalusa Heart Study, 2005. Quartile I represents the lowest birth weight, and quartile IV represents the highest birth weight in children (part A), adolescents (part B), and adults (part C). Covariates included age, sex, race (for total sample), body mass index, and smoking status (for adolescents and adults).

 
Table 2 presents regression coefficients of the WBC count on gestational age-adjusted birth weight and covariates in separate regression models for the study groups. Birth weight was inversely associated with the WBC count in children and adults for both blacks and whites except for black adults, showing an inverse but nonsignificant association. In the combined sample of blacks and whites, birth weight related inversely to the WBC count also in children and adults; a similar trend was noted in adolescents among whites and the total sample, although the association was not significant. In addition to birth weight, significant independent correlates of the WBC count were age (inverse association), race (whites > blacks), and body mass index (positive association) in children and race (whites > blacks), sex (females > males), body mass index (positive association), and smoking (positive association) in adolescents and adults.


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  		Table 2. Regression of White Blood Cell Count on Gestational Age-adjusted Birth Weight and Covariates in Black and White Children, Adolescents, and Young Adults, the Bogalusa Heart Study, 2005

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Information is sparse in the general population regarding the influence of low birth weight on the WBC count, a widely used biomarker of systemic inflammation (12, 18), during different age and growth periods in childhood, adolescence, and young adulthood. The present community-based study demonstrates the inverse association of birth weight with the WBC count in children and adults, independent of confounding factors. It is noteworthy that, by linking low birth weight to the relatively higher WBC count, these findings support the emerging concept of intrauterine imprinting and its pathophysiologic consequences later in life (1, 2).

Although the present observational study, cross-sectional in nature, cannot establish causality or underlying mechanisms, several putative mechanisms link low birth weight to a higher WBC count. Undernutrition in utero is known to cause permanent impairment in growth, structure, and function of, among others, muscle (21, 22), fat (23, 24), endocrine pancreas (25), and vasculature (26) due to adaptive programming, resulting in adverse profiles of the components of metabolic syndrome and related disorders later in life (3, 4, 27). Of interest, in utero muscle growth is retarded in low-birth-weight babies (27); since there is little muscle cell replication after birth (28), these individuals under a nutritionally rich environment later in life will develop a disproportionately high fat mass and related state of chronic low-grade inflammation induced by adipose tissue cells including monocytes (7, 18, 27). Indeed, studies including the present one have shown a positive, independent, and strong relation between adiposity and the WBC count in all age groups (18, 29). However, in view of the observed independent adverse relation between birth weight and the WBC count, there may be still other potential mechanisms operational in programming inflammation pathways in utero.

In this study, birth weight was weakly associated with the WBC count in adolescents. The reason for this is not clear. To our knowledge, no such data are available in the literature for comparison. Because the pubertal period of growth and maturation is characterized by marked changes in fat mass and distribution along with insulin sensitivity (30–33), known strong correlates of inflammation (9, 10), it is likely that low birth weight may not be a strong enough proxy for prenatal factors influencing the WBC count during adolescence. Consistent with previous studies (29, 34), the present study also found race, sex, adiposity, and cigarette smoking to be independent correlates of the WBC count. With respect to the chronic inflammation state and its pathophysiologic consequences, the observed relation in children, adolescents, and adults underscores the value of controlling obesity and smoking behavior in youth.

In conclusion, low birth weight for gestational age is characterized by a relatively higher WBC count, a biomarker of systemic inflammation, in children and young adults. These observations in conjunction with earlier findings support the view that low birth weight, albeit a crude surrogate marker for fetal growth and nutrition, is a potential early risk factor for the emergence of metabolic and hemodynamic disorders and related diseases later in life. As stated by Barker (1) and Barker et al. (3), primary prevention lies in protecting fetal development.


   ACKNOWLEDGMENTS
 
Author affiliation: Tulane Center for Cardiovascular Health, Department of Epidemiology, Tulane University, New Orleans, Louisiana (Wei Chen, Sathanur R. Srinivasan, Gerald S. Berenson).

This study was supported by grants 546145G1 from Tulane University, 0855082E from the American Heart Association, AG-16592 from the National Institute on Aging, and HL-38844 from the National Heart, Lung, and Blood Institute.

Conflict of interest: none declared.


   References
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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