Birth Weight and Long-Term Overweight Risk: Systematic Review and a Meta-Analysis Including 643,902 Persons from 66 Studies and 26 Countries Globally

<div><h3>Background</h3><p>Overweight is among the major challenging health risk factors. It has been claimed that birth weight, being a critical indicator of prenatal developmental conditions, is related to long-term overweight risk. In order to check this important assumption of developmental and preventive medicine, we performed a systematic review and comprehensive meta-analysis.</p> <h3>Methods and Findings</h3><p>Relevant studies published up to January 2011 that investigated the relation between birth weight and later risk of overweight were identified through literature searches using MEDLINE and EMBASE. For meta-analysis, 66 studies from 26 countries and five continents were identified to be eligible, including 643,902 persons aged 1 to 75 years. We constructed random-effects and fixed-effects models, performed subgroup-analyses, influence-analyses, assessed heterogeneity and publication bias, performed meta-regression analysis as well as analysis of confounder adjusted data. Meta-regression revealed a linear positive relationship between birth weight and later overweight risk (<em>p</em><0.001). Low birth weight (<2,500 g) was found to be followed by a decreased risk of overweight (odds ratio (OR) = 0.67; 95% confidence interval (CI) 0.59–0.76). High birth weight (>4,000 g) was associated with increased risk of overweight (OR = 1.66; 95% CI 1.55–1.77). Results did not change significantly by using normal birth weight (2,500–4,000 g) as reference category (OR = 0.73, 95% CI 0.63–0.84, and OR = 1.60, 95% CI 1.45–1.77, respectively). Subgroup- and influence-analyses revealed no indication for bias/confounding. Adjusted estimates indicate a doubling of long-term overweight risk in high as compared to normal birth weight subjects (OR = 1.96, 95% CI 1.43–2.67).</p> <h3>Conclusions</h3><p>Findings demonstrate that low birth weight is followed by a decreased long-term risk of overweight, while high birth weight predisposes for later overweight. Preventing <em>in-utero</em> overnutrition, <em>e.g.</em>, by avoiding maternal overnutrition, overweight and/or diabetes during pregnancy, might therefore be a promising strategy of genuine overweight prevention, globally.</p> </div

Birth weight and later risk of overweight: sensitivity and confounder analyses^*.

<p>Abbreviation: BMI, body mass index; CI, confidence interval</p>*<p>random-effects model</p

Low birth weight (<2,500 g) and subsequent risk of overweight.

<p>ORs for overweight in subjects with birth weights <2,500 g as compared with subjects with birth weights ≥2,500 g. Studies are ordered alphabetically by first author. The point estimate <i>(center of each black square)</i> and the statistical size <i>(proportional area of square)</i> are represented. Horizontal lines indicate 95% confidence intervals. The pooled odds ratio <i>(diamond)</i> was calculated by means of a random effects model. OR, odds ratio; CI, confidence interval.</p

High birth weight (>4,000 g) and subsequent risk of overweight.

<p>ORs for overweight in subjects with birth weights >4,000 g as compared with subjects with birth weights ≤4,000 g. Studies are ordered alphabetically by first author. The point estimate <i>(center of each black square)</i> and the statistical size <i>(proportional area of square)</i> are represented. Horizontal lines indicate 95% confidence intervals. The pooled odds ratio <i>(diamond)</i> was calculated by means of a random effects model. OR, odds ratio; CI, confidence interval.</p

Metabolic parameters in early and later adulthood.

<p>Fasting plasma levels of blood glucose (BG), insulin, insulin/glucose-ratio (IRI/BG), leptin, triglycerides (TG), and cholesterol (Chol) on day 360 of life, <i>i.e.</i>, before the feeding study (<b>A</b>), and day 560 of life, <i>i.e.</i>, at the end of HE/HF feeding study (<b>B</b>). Data are shown as percentages of AGA-in-NL-levels (means ± SEM). Plasma glucose levels after intraperitoneal glucose loading on day 130 of life, <i>i.e.</i>, before feeding study (<b>C</b>), and day 530 of life, <i>i.e.</i>, during high-energy/high-fat (HE/HF) feeding study (<b>D</b>) in rats born small-for-gestational-age, raised in normal litters (SGA-in-NL) or small litters (SGA-in-SL), as compared to rats with normal birth weight raised in normal litters (AGA-in-NL). Data are means ± SD. *<i>p</i><0.05, **<i>p</i><0.01 (one-way ANOVA followed by Tukey’s HSD <i>post hoc</i> analysis).</p

Flow diagram of selection process.

<p>Course of systematic literature review on birth weight and risk of overweight later in life, 1966–January 2011.</p

Relationship between birth weight and risk of overweight.

<p>Continuous relation between birth weight and later risk of overweight, calculated by fractional polynomial regression. Studies are represented by black dots. Grey shading indicates the 95% confidence interval around the fitted line. The model was estimated from a robust regression model based on second-order fractional polynomial (−1, −0.5) functions weighted by/variance.</p

Food intake study in later adult age.

<p><i>Ad libitum</i> energy intake of standard laboratory chow for 30 days (day 470–500 of life) (<b>A</b>), followed by providing a high-energy/high-fat (HE/HF) diet for 60 days (day 500–560 of life) (<b>B</b>). (<b>C</b>) shows overall caloric intake of chow and HE/HF diet throughout food intake study (day 470–560 of life). Absolute and relative body weight changes during the food intake study (day 470–560 of life) (<b>D</b>)<b>.</b> Data are means ± SEM, shown as percentages of AGA-in-NL-levels. *<i>p</i><0.05, **<i>p</i><0.01 (one-way ANOVA followed by Tukey’s HSD <i>post hoc</i> analysis).</p

Correlation analyses.

<p>Relation between plasma levels of leptin and percentage of body fat at day 560 of life (<b>A</b>). Percentage of body fat presented as a function of overall mean food intake (chow+HE/HF) (<b>B</b>). Relation between overall mean food intake (chow+HE/HF diet) and mRNA expression of <i>Npy per</i> unit <i>Pomc</i> (<i>Npy</i>/<i>Pomc</i>) in the arcuate hypothalamic nucleus at day 560 of life (<b>C</b>). Group-specific plots are illustrated (▪: AGA-in-NL; ▴: SGA-in-NL; ▾: SGA-in-SL). Inserts show overall correlation coefficients and significances derived from Spearman’s rank correlation tests.</p

Single neuron preparation using lasercapture microdissection.

<p>Schematic illustration (<b>A</b>) and Nissl-staining (<b>B</b>) of rat hypothalamic nuclei at plane 29 according to Paxinos and Watson <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0078799#pone.0078799-Paxinos1" target="_blank">[44]</a>; scale bar = 100 µm. Insert shows single neuron preparations from the arcuate nucleus (ARC) using Lasercapture microdissection (LMD); scale bar = 25 µm. VMN = ventromedial hypothalamic nucleus, SN = microdissected single neuron.</p