The findings of this observational study suggest that LBW can have deleterious late effects on arterial distensibility, but mainly in women who might suffer premature vascular aging. However, age, sex, BMI and MAP emerged as independent determinants of PWV, unlike BW adjusted for gestational age, which was not independently associated with EVA. Our results also show that individuals with LBW have an increased risk of glucose homeostasis abnormalities and obesity in late adolescence and adulthood. To our knowledge, this study is the first to evaluate the long-term effects of LBW on cardiometabolic risk in Cameroonian subjects.
Evidence suggests that unfavorable in utero environment, induced by a (quantitative and/or qualitative) fetal undernutrition or maternal placental insufficiency, may program the fetus, via epigenetic effects in particular, to subsequent development of CV and metabolic diseases, and to risk factors such as abnormal PWV, obesity and T2DM as phenotypic hallmarks 1, 21, 22, 23.
To provide further insight into possible pathophysiological mechanisms linking LBW to CVD risk in adulthood, we measured aortic PWV which has previously been shown to be a powerful marker of EVA 1, 2, 3 and an independent determinant of CV morbidity and mortality 16, 17. Age and BP are two major determinants of arterial stiffening 1, 2, 3. This was also the case in this study, in which we found that age and SBP were independently associated with PWV, reflecting aortic elasticity loss as a result of chronological aging and hypertension. Stiffening of large arteries, a major consequence of aging, results from alteration of their viscoelastic properties following wall remodeling (from eg. accumulation of calcium, decrease in elastin content, and increase in collagen). This leads to increased arterial stiffness (PWV), with rapid and early wave reflections from peripheral arteries towards the aorta, leading to increased SBP, PP and decreased DBP 15, 16. Consistent with previous observations 1, 17, 18, BMI and male sex emerged as independent determinant of PWV, even in the whole study populations, and especially in the youngest participants age group, 8-27 years old. Moreover, in youngest age group, HR shows significant positive association with PWV after adjusting for age, sex, BMI and MAP. This finding was in keeping with previous observations in young adults 1, 19.
Beyond age, several CV risk factors such as LBW may also promote premature aging of the aorta 1, 2, 3. Although our study did not find an independent association between LBW and PWV, likely as a result of the small sample size of the study, we nevertheless found that in young Cameroonian adults with a history of LBW, overweight and obesity were significantly associated with an increased PWV, even after adjusting for age and MAP. The association between LBW and PWV remains debated. Indeed, Miles et al 5 studied 882 participants in the United Kingdom, in whom increased arterial stiffness was not associated with LBW. By contrast, some studies have also documented stiffer arteries in apparently healthy children and adults with LBW 1, 8, 14, 30.
A major finding of the present study was the markedly increased PWV observed in women with LBW, that persisted even after adjustment for age and MAP compared to those with NBW. This observation corroborates that of Martyn et al 2 on 338 individuals born between 1939 and 1940, in whom intrauterine growth retardation was associated with increased aorto-iliac and femoro-popliteal-tibial PWV by the age of 50 years, regardless of adult lifestyles. The putative mechanisms underlying the increase in arterial stiffness in adulthood include be changes in angiogenesis during critical phases of intrauterine life caused by episodes of fetal growth inhibition and local hemodynamic anomalies 1, 2, 3, 4 and early endothelial dysfunction as well as premature remodeling of large arteries, ascribed to mechanical and growth factors, fetal protein deficiency, and detrimental effects of cytokines and proteases 1, 2, 13, 14.
We also observed that the MAP of participants with LBW for gestational age was approximately 2 mmHg higher than that of NBW participants (≥ 3000g). However, this difference was not statistically significant. Nevertheless, this finding is consistent with data in the literature, which reported an association between LBW and increased BP in adulthood 1, 2, 3. However, this association is debated 8, 33, 34. In the present study the prevalence of hypertension was higher among participants with NBW compared to those with LBW. This finding is inconsistent with observational studies that reported an increased risk of adult-onset hypertension in Caucasians with LBW 1, 2, 3, 4, and also with data from a study conducted in Nigeria, showing a high prevalence of hypertension in participants born during the Biafra war (1968-1970) and exposed to severe famine and materno-fetal and infantile malnutrition, compared with controls born in the same region just before the war, i.e. between 1965-1967 31. Our findings, although based on a small sample of subjects, are nevertheless in line with data from international epidemiological surveys 8, 9, 10.
A component of hypertension in adulthood was associated with unfavorable intrauterine conditions in mid- and late gestation, leading to disproportionate fetal growth 1, 2, 3, 4. The presumed role of fetal and/or early childhood malnutrition in driving the late burden of hypertension has not been examined in Africa, neither in Cameroon nor in other sub-Saharan African countries. Further large-scale studies are needed to better assess the impact of uterine malnutrition and LBW on the burden of hypertension in adulthood.
Of note, participants with LBW had an increased prevalence of overweight/obesity and visceral obesity. Our findings are consistent with previous observations showing a greater propensity to develop central and visceral obesity in adulthood in subjects with LBW 20, 21, 23, 31, 35, 36. Despite LBW and substantial risk of early postnatal underweight, former fetal-malnourished fetuses have higher subsequent obesity indices than controls with NBW, suggesting potential catch-up growth in adolescence of early adulthood. The latter, apparently beneficial, probably reflects rapid weight gain associated with poor linear growth, defining a phenotype of "obese stunted" subject with unfavorable body composition, including fat accumulation (especially visceral) and sarcopenia without height gain 23, 26, 31, 35, 36.
Another relevant finding of the present study is the high rate of glucometabolic abnormalities in subjects with LBW, globally and particularly in those with overweight/obesity in adulthood. This finding is in line with previous observations showing that subjects with LBW are at increased risk for incident metabolic syndrome 21, 22, 23 and T2DM 22, 37, 38, 39. This suggests that insulin resistance acquired in the context of visceral obesity is insufficiently compensated by compensatory hyperinsulinemia in many of these subjects with LBW, and that their insulin-secretory function is also less efficient in counteracting these effects of obesity 23, 37, 39. Experimental models suggest that protein deficiency resulting from materno-fetal nutritional imbalance may lead to developmental programming of carbohydrate homeostasis abnormalities in adulthood 38, 40.
This study has several obvious limitations. First, this was a cross-sectional study with limited sample size and hence limited statistical power to detect magnitude of the effects of BW on risk of CV and metabolic diseases and exhibiting their associated major risk factors in adulthood in the general Cameroonian population. Further studies are needed, relying on larger samples size and including other regions of Cameroon. Second, several potentially confounding factors, such as socio-economic status, lipid profile, glycated hemoglobin, insulinemia, c-reactive protein, were not assessed due to financial and logistical constraints. Last, BW represents a single measurement and does not account for in utero growth trajectory and is not adjusted to parents’ heights. Proportionality indices assessing body size including body length, BMI at birth, and/or birth’s ponderal index (birth weight/birth length³), more accurately reflect fetal growth trajectory and may help differentiate fetuses who are constitutionally small for gestational age from fetuses who failed to reach their in utero growth potential, were not available for this survey 40. A strength of the present study is its originality and its design as stringent as possible, and the use of validated standard procedures to assess the variables of interest.