Published online September 1, 2006
PEDIATRICS Vol. 118 No. 3 September 2006, pp. 1118-1123 (doi:10.1542/10.1542/peds.2006-0740)
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ARTICLE

Little Evidence for Early Programming of Weight and Insulin Resistance for Contemporary Children: EarlyBird Diabetes Study Report 19

Alison N. Jeffery, MSca, Brad S. Metcalf, BSca, Joanne Hosking, PhDa, Michael J. Murphy, FRCPb, Linda D. Voss, PhDa and Terence J. Wilkin, MDa

a Department of Endocrinology and Metabolism, Peninsula Medical School, Plymouth, United Kingdom
b Department of Biochemical Medicine, Ninewells Hospital, Dundee, United Kingdom


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. The aim of this study was to evaluate whether adaptive responses made to the uterine or very early infant environment are affecting the current metabolic health of young children in the United Kingdom.

METHODS. Participants were 300 healthy children and their parents from the EarlyBird Diabetes Study cohort. Children were recruited from randomly selected schools at 5 years of age. Retrospective measures were maternal prepregnancy weight (n = 230), maternal fasting glucose levels at 28 weeks of pregnancy (n = 27), birth weight, and infant weight at ages 3 and 6 weeks. Prospective measures were insulin resistance, height, weight, and percentage of body fat (sum of 5 skinfold measurements) at ages 5, 6, 7, and 8 years.

RESULTS. Maternal third-trimester fasting glucose levels were associated positively with birth weight but were not associated with either weight or insulin resistance for the same children at 8 years. Birth weight was unrelated to insulin resistance at 8 years. There were no relationships between weight change in the first weeks of life and weight, percentage of fat, or insulin resistance at 8 years. Longer breastfeeding correlated inversely, although weakly, with percentage of body fat for boys only. Current weight was correlated with insulin resistance at 8 years.

CONCLUSIONS. For these contemporary children, neither the gestational environment nor early postnatal growth predicted insulin resistance, which was best predicted by current weight. There was no evidence that predictive adaptive responses made by the fetus or infant affected the child's weight or insulin resistance later in childhood.

Key Words: birth weight • body composition • body mass index • breastfeeding • children • fetal programming • insulin resistance • metabolic syndrome • obesity • weight

Abbreviations: HOMA-IR—homeostasis model assessment-insulin resistance

Genetic susceptibility to the metabolic syndrome can have changed little in recent decades, but environmental risk has increased dramatically. The industrialized world is experiencing an epidemic of childhood and adult obesity,1, 2 associated with an exponential increase in the incidence of type 2 diabetes mellitus,3 which increasingly is being diagnosed in childhood and adolescence.4 Identification of a critical period of development that may trigger later obesity and poor health has attractive implications for researchers, clinicians, and public health policymakers.

The predictive adaptive response, a term coined by Gluckman and Hanson,5 is the means through which an environmental interaction early in life would lead to selective advantage in the predicted adult environment. Gene-environment interactions have allowed animals to adapt to differing environments, with variations in phenotypes conferring particular survival advantages in a given environment. The benefit conferred by these adaptations may not be obvious at the time, relating to a predicted environment. In this way, the mother can inform her fetus of a future adverse environment, allowing him or her to make a phenotypic change that is adaptive for the predicted environment. Problems arise when the adult environment turns out to be different from that predicted. The mismatch associated with obesity has emerged recently; the environment has changed, but the genes have not.

The fetal origins6, 7 and thrifty phenotype8 hypotheses proposed that poor nutrition in utero was associated with subsequent cardiovascular disease and type 2 diabetes. The mechanism suggested involved development of an enhanced ability to store fat to sustain the individual during a lifetime of predicted suboptimal nutrition. This was followed by the observation that individuals at greatest risk were those who were born light but subsequently gained excess weight and "crossed centiles,"9 which implicated both prenatal and postnatal nutrition. Singhal and Lucas10 suggested that early growth acceleration (through overfeeding in the first 2 weeks of life) explained the adverse metabolic effects of a nutrient-enriched diet (the growth acceleration hypothesis).

A limiting factor of the original programming studies was their historical nature. The period on which they were based spanned environmental changes the like of which humankind had probably never experienced before, and causality was inferred with little allowance for a period effect. Contemporary prospective cohort studies are needed to distinguish the potential contributions of genes, gestation, and postnatal nutrition. This study tested some predictions of the programming hypotheses in a contemporary cohort of young children in the United Kingdom, in the EarlyBird Diabetes Study. This article presents results for the EarlyBird Study children at the age of 8 years, extending the data reported by Wilkin et al11 for the same children at 5 years. In addition, it examines the effects of fasting glucose levels during pregnancy and weight in early infancy.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Design
The EarlyBird Diabetes Study is a prospective, nonintervention, cohort study designed to answer the question, Which children develop insulin resistance, and why? The study is ongoing in the city of Plymouth, United Kingdom, and full details of the protocol were published elsewhere.12 In brief, 307 healthy children (170 boys and 137 girls; 98% white) were recruited in 2000 and 2001, at a mean age of 4.9 ± 0.3 years, from randomly selected schools, stratified according to socioeconomic status. Informed consent was obtained from the parents at entry into the study, and assent was obtained from the children at each visit. Attrition rates have been low and, 4 years later, the study retains 269 children (88%) of the original cohort, with full sets of results. Local research ethics committee approval was obtained in 1999. Five sets of twins were excluded from analyses for this article, along with 10 children born preterm (before 37 completed weeks of gestation). Therefore, this article (EarlyBird Diabetes Study report 19) presents results on 137 boys and 112 girls.

Measures
Baseline data on children and parents included family medical history and socioeconomic details; early feeding history; height (Leicester Height Measure; Child Growth Foundation, London, United Kingdom); weight, expressed as SD scores derived from gender-specific 1990 United Kingdom reference curves13 with Tanita Solar 1632W electronic scales (Tanita, West Drayton, United Kingdom); adiposity, based on the percentage of body fat from the sum of 5 skinfold measurements (skinfold calipers; Holtain, Crymych, United Kingdom); and BMI. Weight SD and BMI at 8 years were correlated (r = 0.89). Analyses used weight SD to provide consistency with infant weights. Annual measurements of fasting glucose and insulin levels, for measurement of insulin resistance, were calculated with the homeostasis model assessment-insulin resistance (HOMA-IR), which has been validated in epidemiologic studies of children.14 These measurements are repeated annually for the children. Results are now available for the children at ages 5, 6, 7, and 8 years.

Additional Data
Details of each mother's pregnancy with the EarlyBird Study child were obtained from the hospital obstetric notes. Reported prepregnancy weight was recorded for 223 women. According to hospital protocol, 27 women with random blood glucose measurements of >6.5 mmol/L at 28 weeks subsequently underwent fasting blood glucose measurements. For 26 of these women, fasting glucose levels were normal (<6.1 mmol/L). The women were thus considered to have normal glucose regulation and were included in the analyses.

Weight at 3 weeks was available from health visitor records for 74 boys and 56 girls. Gestational age and weight at birth (all children) and at 6 weeks (121 boys and 106 girls) were available from the Plymouth Child Health Registry. These weights were adjusted for exact age and are presented as SD scores.

Statistical Analyses
SPSS for Windows (version 11.5.1; SPSS, Inc, Chicago, IL) was used for statistical analyses. Weight was distributed normally. HOMA-IR was transformed logarithmically to achieve a normal distribution. Pearson's product-moment correlations were used to study associations between variables. Partial correlation was used to measure the association between insulin resistance and birth weight after controlling for the colinearity of current weight. Regression analysis was used to study the trends in birth weight and weight at 8 years. Results are reported separately according to gender, where appropriate, because of the intrinsically higher insulin resistance of the girls, even after accounting for physical activity and fat mass.15

Power Estimates
Complete data sets at 8 years of age were available for 131 boys and 104 girls. The numbers were sufficient to detect correlations of r = 0.24 for the boys and r = 0.27 for the girls at the .05 level, with 80% power.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Maternal Weight, Third-Trimester Glucose Levels, and Pregnancy Outcomes
Thirty-six percent of the EarlyBird Study mothers were overweight or obese (BMI: ≥25 kg/m2) before pregnancy. At the age of 8 years, 19% of the children were overweight or obese. All children had glucose and insulin measurements within the normal range (maximal recorded levels: 5.6 mmol/L and 12.3 mU/L, respectively), and 99% had HOMA-IR levels within 1 SD of the mean.

The correlations between the mother's prepregnancy weight and the child's weight at birth, weight at 8 years, and HOMA-IR at 8 years are shown in Table 1. Maternal third-trimester fasting glucose levels were associated with birth weight but not with either weight or insulin resistance for the child at 8 years. There was no difference in children of mothers who did or did not have fasting glucose measurements during pregnancy, with respect to either insulin resistance (t test: t = 0.38; mean difference: 0.05; P = .72; degrees of freedom = 230) or weight SD (t = –1.15; mean difference: –0.28; P = .25; degrees of freedom = 230) at age 8. Weight tracked from birth to 8 years of age for both genders, although more strongly for the boys (boys: r = 0.39; P < .001; girls: r = 0.19; P = .048). We found no correlations between birth weight and insulin resistance at 8 years, for either boys (r = –0.04; P = .62) or girls (r = –0.04; P = .37).


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  		TABLE 1 Pearson's Correlations Between Maternal and Child Measures

 
Early Weight, Weight Gain, and Outcomes
Weight in infancy was associated positively with later weight for the boys only (Tables 2 and 3). For neither gender was there an association between weight in infancy and adiposity or insulin resistance at 8 years. Changes in weight between birth and 3 or 6 weeks were unrelated to later outcome measures.


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  		TABLE 2 Pearson's Correlations Between Weights at 3 and 6 Weeks and Weight and Adiposity at 8 Years

 

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  		TABLE 3 Partial Correlations of Weights at 3 and 6 Weeks and Insulin Resistance at 8 Years, Controlled for Weight at 8 Years

 
Breastfeeding and Outcomes
Duration of breastfeeding was unrelated to weight, BMI, and insulin resistance at 8 years for either gender. There were, however, weak inverse correlations between duration of breastfeeding and adiposity for the boys at each age (r = –0.16 to –0.19; P < .05), independent of social class and birth weight. This relationship was not seen for the girls.

Current Weight and Outcomes
Eighteen percent of boys and 23% of girls were overweight (BMI: ≥91st percentile) at 8 years. As expected, weight at both 5 and 8 years provided the strongest correlation with insulin resistance at 8 years (Table 4). When the contributions of weight and weight change between birth and 8 years to insulin resistance were examined in a regression model, weight change did not improve the prediction of insulin resistance once current weight was known (Table 5).


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  		TABLE 4 Pearson's Correlations of Weight and Weight Change From 0 to 8 Years With Insulin Resistance at 8 Years

 

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  		TABLE 5 Regression Model Adding Weight Change to the Prediction Model for Insulin Resistance After Accounting for Current Weight

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We were unable to demonstrate any consistent impact of pregnancy, birth weight, or early growth on insulin resistance in contemporary 8-year-old children. More than one third of the mothers were overweight before their pregnancy, but neither their prepregnancy weight nor their glucose levels during the last trimester of pregnancy affected their child's insulin resistance. Similarly, and in contrast to the historical data on which the fetal programming hypotheses were based, birth weight for these contemporary children was unrelated to subsequent insulin resistance. The findings contrast with those of Lawlor et al,16 who demonstrated an inverse association between birth weight and insulin resistance for slightly older British children. However, Ong et al17 could demonstrate this association only for children in the highest current BMI tertile, which again suggests the overriding importance of current weight.

Changing demographic features are one reason for the diminishing importance of birth weight. Low birth weight at term (<2500 g) is now uncommon in the white population of the United Kingdom (<2.5% of term infants born in Plymouth in 1995 weighed <2500 g), and recently birth weights have been increasing, rather than decreasing.18 The fetal origins hypothesis predicts decreasing metabolic risk with increasing birth weight; therefore, an alternative explanation clearly is needed.

The growth acceleration hypothesis19, 20 shifted emphasis from the prenatal period to the postnatal period, arguing that birth weight was as likely to be a surrogate measure for postnatal factors as for prenatal factors. In the early 1980s, Lucas and colleagues initiated a unique series of randomized, controlled trials examining the effects of infant feeding on subsequent outcomes.21–23 Although outcomes were not always analyzed according to the intention to treat, there was clear evidence that overfeeding during early infancy (causing the infant to cross growth percentile lines) was associated with later weight excess and metabolic disturbances. The studies by Lucas,21–23 in combination with earlier observations on animals,24–26 identified the first 2 weeks of life as critical for programming, irrespective of body size. In the present work, we studied the effects of weight at 3 and 6 weeks of age on outcome measures at 8 years. We found a modest relationship with weight for the boys and a tendency toward a relationship with insulin resistance for the girls. The age of participants at review in the studies conducted by Lucas21–23 was 13 to 16 years, and we will be in a position to reanalyze the relationships as the EarlyBird Study cohort achieves the same ages.

The implications of the growth acceleration hypothesis are important for breastfeeding. The relationship between breastfeeding and protection against later obesity and metabolic disease has been well researched, and systematic reviews confirmed a weak beneficial effect.27, 28 The benefit may be attributable to better energy regulation in breastfed infants, compared with bottle-fed infants. The introduction of solid foods increases the energy density of the diet29; therefore, breastfeeding for longer periods also may improve energy regulation. Consistent with this, we found the duration of breastfeeding to be associated weakly with adiposity for the boys, which suggests that breastfeeding for longer periods may protect children against later adiposity.

The results presented here are subject to limitations. First, the end point for these analyses was 8 years, whereas the original programming hypotheses were generated with data for middle-aged or elderly participants. Differences in weight or metabolic health variables may become more obvious once these children become adolescents or young adults. The EarlyBird Study is well placed to evaluate the relationships when the cohort is older. Some early markers of metabolic risk (triglyceride, high-density lipoprotein cholesterol, and sex hormone-binding globulin levels) have already been reported for the EarlyBird Study cohort.15 Second, the numbers in this study are small, compared with some of the historical epidemiologic cohorts, particularly with subdivision according to gender. However, sufficient power was available to detect important relationships between early weights and later insulin resistance. The data on maternal pregnancy and infant feeding were gathered retrospectively. The number of women with fasting pregnancy glucose measurements was small, and the group might have represented mothers with greater insulin resistance (correlation with maternal HOMA-IR 5 years later: r = 0.45; P = .08). However, there was no difference in insulin resistance or childhood weight between children of mothers who did or did not have fasting glucose levels recorded, which suggests no demonstrable programming effect at age 8 years.

Being unable to find evidence for the fetal programming hypotheses, we turned to the children's current weight and concluded that metabolic risk for contemporary children is associated predominantly with their current weight. Their gain in excess weight during the first years of life is such that the immediate postnatal period now seems to exert little effect. Lifestyle factors operating throughout childhood may be more important than the legacy of the fetal and early infant environments. The findings are consistent with those of Kinra et al,30 who concluded that obesity risk for children at 7 years of age accrues gradually over childhood, with no evidence of an early critical window.


   ACKNOWLEDGMENTS
 
The EarlyBird Study is supported by Diabetes United Kingdom, GSK, Abbott Laboratories, Astra-Zeneca, Ipsen, Smith's Charity, Roche Pharmaceuticals, the Henry Smith Foundation, the Child Growth Foundation, Eli Lilly, Unilever, Pfizer, and the EarlyBird Diabetes Trust.

We acknowledge gratefully the help of EarlyBird Study nurses Rosemary Snaith and Karen Brookes and the EarlyBird Study children and their families.


   FOOTNOTES
 
Accepted Apr 28, 2006.

Address correspondence to Alison N. Jeffery, MSc, EarlyBird Research Centre, Level 12, Derriford Hospital, Plymouth PL6 8DH, United Kingdom. E-mail: alison.jeffery{at}pms.ac.uk

The authors have indicated they have no financial relationships relevant to this article to disclose.


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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

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