Growing evidence suggests that low birth weight (LBW) adjusted for gestational age could adversely influence arterial stiffness, a marker of early vascular aging (EVA) measured by aortic pulse wave velocity (PWV), and blood pressure (BP) regulation 12345, thereby increasing risk of cardiovascular (CV) events in adulthood 34567891011. Indeed, an inverse relationship between birth weight (BW) and BP has been demonstrated, with higher risk of hypertension in adulthood 12678910. This association could be related either to renal organogenesis abnormalityor to decreased elastin synthesis within large arteries’ wall during fetal life 6121314. In individuals with LBW, early remodeling of large arteries, such as the aorta, might occur during adult life, with increase in caliber and wall remodeling, with a decrease in elastic fibers content and an increase in collagen fibers in the media. This remodeling of large arteries’ wall was attributed to mechanical effects and growth factors, as well as cytokines and/or proteases 2121314. Several studies have shown that the loss of elasticity in large arteries, leading to EVA, the latter characterized by raised arterial stiffness as measured by aortic pulse wave velocity (PWV), is an independent predictor of CV risk and overall mortality 14151617181920. It was also observed that individuals with fetal malnutrition and LBW were at increased cardiometabolic risk in adulthood, including incident type 2 diabetes mellitus (T2DM), obesity, and metabolic syndrome 212223.

In Cameroon, despite a large number of subjects with a history of LBW, mostly caused by foetal growth retardation and materno-fetal malnutrition during high-risk pregnancies 24, to the best of our knowledge, no study has explored the late effects of LBW on EVA and cardiometabolic phenotypes in Cameroonian adolescents and adults. The present study was aimed to address this issue.

This was a cross-sectional study performed at the Cameroon Heart Institute, based in Douala, Cameroon between November 2017 and June 2018. We consecutively recruited apparently healthy Cameroonian individuals aged 15 to 30 years old, all non-smokers, in whom full data on BW and gestational age at birth were documented in the register of births. Individuals were excluded if they were taking medications or had any medical conditions that may have affected growth, maturation, physical activity, nutritional status, or their cardiometabolic health. Subjects with missing information for any of the variables were also excluded. All participants completed a validated questionnaire on personal and familial histories of CV or metabolic diseases, socio-demographics, and lifestyle habits. Anthropometric, hemodynamic and biological parameters collected included height, weight, waist circumference, BP, heart rate (HR), PWV, and fasting capillary blood glucose.

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 1212223.

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 123 and an independent determinant of CV morbidity and mortality 1617. Age and BP are two major determinants of arterial stiffening 123. 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 1516. Consistent with previous observations 11718, 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 119.

Beyond age, several CV risk factors such as LBW may also promote premature aging of the aorta 123. 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 181430.

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 1234 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 121314.

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 123. However, this association is debated 83334. 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 1234, 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 8910.

A component of hypertension in adulthood was associated with unfavorable intrauterine conditions in mid- and late gestation, leading to disproportionate fetal growth 1234. 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 202123313536. 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 2326313536.

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 212223 and T2DM 22373839. 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 233739. Experimental models suggest that protein deficiency resulting from materno-fetal nutritional imbalance may lead to developmental programming of carbohydrate homeostasis abnormalities in adulthood 3840.

This study suggests that, whereas LBW is associated with increased aortic stiffness in young adulthood, mainly in women, the association was predominantly driven by age and blood pressure. Once adult, subjects with LBW exhibited higher obesity indices and poorer glucose homeostasis. Further large-scale studies are needed to assess the impact of BW and body size on arterial stiffness and metabolic disorders in later life.