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We performed a systematic literature review on the associations between birth size and abdominal adiposity in adults, while also investigating the role of the adjustment for adult body mass index (BMI). MEDLINE, Scopus, Web of Science, LILACS and SciELO databases were searched for articles published up to February 2013. Only prospective studies were included. After screening 2,570 titles, we selected 31 publications for the narrative synthesis, of which 13 were considered to be of high methodological quality. Six main indicators of birth size were identified, and birth weight (BW) was the most extensively studied. Most studies relied on anthropometric measurements as proxies for abdominal fatness or as indicators of body fat distribution. Few studies assessed abdominal adiposity through imaging methods, generally with small sample sizes. Eleven articles could be included in the meta-analyses. BW was found to be positively associated with waist circumference in adulthood, but the association disappeared after adjustment for adult BMI. In contrast, there was no association between BW and waist-to-hip ratio, whereas a strong negative association became evident after controlling for adult BMI. In conclusion, BW seems to be associated with larger adult size in general, including both waist and hip circumferences. The marked change in coefficients after adjustment for adult BMI suggests that post-natal growth strongly affects relative central adiposity, whereas BW per se does not play a role. Given the potential impact of post-natal growth, further research is needed to identify different growth trajectories that lead to abdominal adiposity, as well as studies on interactions of foetal and post-natal growth patterns.
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Obesity is defined as an excess of body fat, traditionally classified based on the body mass index (BMI) . Its prevalence nearly doubled from 1980 to 2008, reaching epidemic levels and affecting countries independently of income or developmental levels . Several studies have shown associations between BMI and adverse outcomes, such as mortality and cardiovascular diseases (CVD) [3-7]. However, BMI alone does not account for regional distribution of body fat, which has been pointed as a key correlate of the health risk associated with overweight and obesity [8, 9].
Central fat accumulation, and in particular intra-abdominal or visceral fat depots, has been identified as an independent risk factor for insulin resistance, CVD and hypertension [10-14]. Many methods are available for central body fat assessment . Anthropometric measures and derived indicators, such as waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR) and ratio of subscapular to triceps skin-folds (STSR), are largely used as proxies for abdominal fat in order to assess risk for adverse outcomes [9, 16].
In a recent review, Seidell  reported an increased risk of all mortality related to WC and WHR, throughout the range of adult BMIs. WC and WHR have been shown to be better markers of metabolic risk than BMI, among both sexes and different ethnic groups [18-20]. However, WC and WHR cannot capture the distinct components of abdominal fat depots . Developing of imaging methods, such as computed tomography, magnetic resonance imaging (MRI) and ultrasound, allowed assessing the different risks associated with visceral and subcutaneous abdominal fat [22, 23]. Visceral rather than subcutaneous fat has been associated with insulin resistance and type 2 diabetes, atherogenic dyslipidaemia and CVD, among others .
Following the hypothesis of the early onset of adult diseases [24, 25], several studies assessed the association between size at birth and adult obesity or its comorbidities [26-29]. According to this hypothesis, early life experiences may induce permanent changes in organ functions, through a process of biological programming [30, 31]. The prenatal phase is referred to as ‘critical period’ when adverse events may have a lifelong effect on later body composition and contribute to the development of obesity .
Birth weight (BW) is largely used as a proxy for intrauterine growth, and its relation with adult BMI has been extensively studied [26, 33]. BW distributions are remarkably different across developed and developing countries, and the associations between BW and later adiposity may differ in these populations . Although most studies showed positive associations when BW is treated as a continuous variable , some have also raised the hypothesis that low BW infants may be at higher risk of adult obesity and its comorbidities, compared with those in the normal range [35, 36]. Interpretation of the existing literature is complex because few studies separated lean from fat mass in adults, and even fewer examined fat distribution. Those who did so suggested that low BW infants tend to develop central adiposity [36, 37]. In 2003, Rogers and EURO-BLCS Study Group  identified 10 publications dealing with the association between BW and abdominal adiposity, showing a positive association with WC but little evidence of an association with WHR or STSR. Since this review, many other studies have been published on this topic.
In the present study, we aimed to (i) systematically review the literature on the associations between birth size and abdominal adiposity in adults, updating the review carried out by Rogers and EURO-BLCS Study Group  and extending it to other measures of birth size in addition to BW; (ii) perform a meta-analysis in order to summarize the effects of birth size on abdominal adiposity in adults and (iii) investigate the role of adjustment for adult BMI in the association between birth size and abdominal adiposity in adults.
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Studies in animal models have shown that the metabolism of adipose, lean and hepatic tissues may be programmed by maternal nutrition during gestation and lactation [79, 80]. Epidemiological evidence from the last decades has shown that environmental exposures from conception to adulthood influence the susceptibility to obesity and chronic diseases . However, the relevant mechanisms in humans are unclear, and the associations between birth size and later adiposity have been inconsistent. An effect of early life exposures on body fat distribution, especially on the central accumulation of fat, could lead to altered risks for obesity-related metabolic diseases in adult life.
In 2003, Rogers and EURO-BLCS Study Group  carried out a literature review and reported that several studies had found positive associations between BW and WC. Unadjusted analyses showed little evidence of direct association with measures of relative distribution of fat, such as WHR or STSR. Analyses adjusted for current body mass showed consistent evidence of negative association between BW and STSR, but less consistent evidence of negative associations with WHR. The authors also highlighted the heterogeneity of the subjects studied, the variability in the indicators of fat distribution and the generally small sample sizes.
A literature review performed by Fall  addressed studies relating BW to later body composition in adults. The results were mixed. Whereas some studies showed positive associations between BW and WC or WHR, others failed to detect an association. Additionally, some studies found that low BW was associated with higher WHR after adjustment for current BMI or weight. The author concluded that there is some evidence that low BW contributes to abdominal fatness. Although presenting a comprehensive perspective of the evidence for the early determinants of adiposity in later life, the review was not systematically performed and reported.
We performed a systematic review of the literature on associations between birth size and adult abdominal adiposity, including several measurements of both exposures and outcomes. We also presented comprehensive estimates of associations between BW and WC/WHR, and used meta-analysis to obtain pooled effects, with and without adjustment for adult BMI.
Our results may be summarized as follows. Pooling both sexes, we found a positive association between BW and WC. The overall estimate obtained through meta-analysis presents moderate heterogeneity among studies, and in the qualitative narrative review, it appeared that the association was stronger among men. However, there was little heterogeneity associated with sex in the meta-analyses. Regarding the relative distribution of fat, there is no evidence of association between BW and WHR, in either sex. Our estimates present low heterogeneity among studies in both sex-combined and sex-stratified analyses.
The present results are compatible with a positive association between BW and overall adult body size, including WC and HC, but do not support a specific effect of BW on central adiposity.
The reviewed articles differ in many ways: from the definition of exposures and outcomes, to the study design, age composition of samples and potential confounders. Most studies were carried out in high-income countries from Europe and North America. This must be taken into account when interpreting the results of the present review because life-course research from low- and middle-income countries may show different patterns of associations and confounders in comparison to findings from high-income countries [36, 83].
We identified six main indicators of birth size, of which BW was the most extensively studied. This can be explained by the fact that studies from high-income countries often rely on birth records. BW has been historically considered as an important indicator of prenatal conditions, and as a predictor for survival, growth and development later in life [26, 84].
Most studies included in the present review relied on anthropometric measurements as proxies for abdominal fatness and/or indicators of body fat distribution. We find that a distinction between absolute and relative measures of abdominal fatness is useful in interpreting the results of different studies. WC represents an absolute measure of abdominal fat, being considered as the best anthropometric correlate of absolute amount of VAT .
Two ratio measures are often used as indicators of relative distribution of fat, comparing central to peripheral fat. The WHR is used to assess the ratio of intra-abdominal to peripheral fat [9, 33] because HC reflects fat deposition in the buttocks, as well as pelvic size and gluteal muscle . A second anthropometric ratio is the STSR, or ratio between a centrally located skin-fold (subscapular) and a peripheral skin-fold (triceps), thus reflecting the ratio of truncal to peripheral subcutaneous fat . Therefore, whereas WHR and STSR both reflect ratios of central or truncal to peripheral fat, they have different anatomical connotations.
Highly precise measurements of relative body fat distribution can also be obtained through imaging methods. For example, Kaess et al.  demonstrated in a large community-based sample that the VAT/SAT ratio measured by computed tomography is a correlate of cardiometabolic risk above and beyond obesity defined using BMI and absolute visceral fat mass. However, we identified few studies that reported measurements obtained through imaging methods. Those that did so generally used small sample sizes, probably because of the high costs of the methods and, for computed tomography, the risks associated with radiation exposure .
We assessed the association between BL and relative central adiposity measured through STSR. The number of studies was insufficient for meta-analysis; however, based on the narrative synthesis, there was evidence of an inverse association, but only among men. We are not aware of any previous reviews on this topic, but a recent review on BL and adult BMI or overweight or obesity found that eight of nine studies failed to detect an association . A potential biological mechanism for these findings is that BL would contribute primarily to lean mass but not to fat mass , and therefore would not affect BMI as a whole, nor lead to central adiposity.
Despite the small number of articles, we highlight the consistent positive association between BW and HC in both men and women. Several studies have shown that HC presents a strong inverse association with the cardiovascular risk, once the deleterious effect of WC has been accounted for [87-89]. The protective effect of larger hips in relation to WC seems to be related to the regulation of fatty acid release and uptake, and a beneficial adipokine profile related to gluteofemoral adipose tissues .
Few studies addressed the association between BW and Ponderal index/BMI at birth, SGA or BW for gestational age. We could not identify clear patterns for these associations. The results presented are also inconclusive.
We now address the consequences of adjustment for adult BMI when analysing the association between BW and central adiposity. Previous studies have shown how such adjustment affects the association between BW and later measurements, such as blood pressure [91-93].
We start with the association between BW and WHR. There was no statistical evidence of association when adult BMI was not adjusted for, whereas a strong negative association emerged after adjustment. This statistical artefact has been described as the ‘reversal paradox’  in which the association between two variables is reversed, diminished or enhanced by the adjustment for another related variables . Adult BMI is not a true confounder in the association between BW and abdominal adiposity in adulthood because it is not independently related to both variables. In fact, when both BW and BMI are in the same model with outcomes related to non-communicable diseases, BW often becomes negatively associated with the outcome. This should be interpreted as an effect of post-natal weight gain, rather than a protective effect of BW per se , given that in the analyses that were unadjusted for BMI there was no effect of BW [97-100]. The results of our meta-analyses of WHR clearly show that this is the case.
An analogous finding was observed in the meta-analysis for absolute abdominal adiposity, measured through WC. BW showed a positive association with WC in both sexes before adjusting for adult BMI, but there was no statistical evidence of association after adjustment. The apparent disappearance of the association after adjustment would also be consistent with the reversal paradox, signalling that post-natal growth also plays a role. These findings from the meta-analyses must be interpreted with caution. We identified moderate heterogeneity for the overall effect, although performing a meta-regression is not a recommended option considering the small number of studies included .
In summary, the meta-analyses showed that the adjustment for adult BMI leads to disappearance of the initially positive association between BW and WC, showing that both BW and post-natal growth are important for absolute central adiposity. In contrast, we observed a negative association with WHR after controlling for adult BMI, whereas unadjusted analyses showed no statistical evidence of association. These findings could suggest that post-natal growth is important in relative central adiposity, whereas BW does not play a role. Therefore, BW could be associated with larger adult size in general, including both waist and HCs.
This is consistent with results from the cohorts showing a stronger association between BW and lean mass than with fat mass, which could be due to either greater concentration of lean mass in non-abdominal regions or accumulation of fat mass in the abdomen .
Our review has some limitations. All studies included in the analyses are observational; therefore, we cannot rule out the possibility that results were affected by residual confounding. Most articles failed to describe follow-up rates or non-response rates, so we could not determine if selection bias may have influenced their findings. Control for confounding varied widely across studies, and some of them did not present estimates adjusted for important confounders such as socioeconomic status and maternal characteristics. We identified very few studies from low- and middle-income countries, where the effect of birth size on later adiposity may be different than that observed in high-income countries [36, 83].
The small sample sizes of some studies, especially those using imaging methods, could explain the lack of statistical associations; it is noteworthy that none of the articles in the review reported power calculations. Lastly, we could not obtain a pooled effect for several of the associations because of the limited number of studies assessing the same combination of exposure and outcome. Also because of the few studies available, we could not perform meta-regressions to better explore the heterogeneity between studies.
The strengths of this review include its systematic nature, the restriction to studies with reliable ascertainment of size at birth and the overall proportion of high methodological quality studies. Most of the studies reviewed used standard protocols for assessment of anthropometric measurements [102, 103], so that these were generally comparable across studies. We were able to compare pooled effects between those studies that adjusted for adult BMI and those that not, as adult BMI is an important factor in the causal path between BW and abdominal adiposity. Finally, publication bias was found not to be important for most outcomes when we examined the effect of study size on the estimates.
In conclusion, epidemiological and clinical studies show that abdominal obesity is an important risk factor for various diseases. Because dietary interventions for obese patients have limited success [19, 104], it is also important to identify early risk factors for later abdominal adiposity that may be amenable to intervention through a life course approach. Given the potential impact of post-natal growth, further research is needed to identify different growth trajectories that lead to abdominal adiposity, as well as studies on interactions of foetal and post-natal growth patterns . More studies from low- and middle-income countries are needed, and in particular more studies using imaging methods to assess abdominal adiposity.