Risk factors during first 1,000 days of life for carotid intima-media thickness in infants, children, and adolescents: A systematic review with meta-analyses.

Background The first 1,000 days of life, i.e., from conception to age 2 years, could be a critical period for cardiovascular health. Increased carotid intima-media thickness (CIMT) is a surrogate marker of atherosclerosis. We performed a systematic review with meta-analyses to assess (1) the relationship between exposures or interventions in the first 1,000 days of life and CIMT in infants, children, and adolescents; and (2) the CIMT measurement methods. Methods and findings Systematic searches of Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), and Cochrane Central Register of Controlled Trials (CENTRAL) were performed from inception to March 2019. Observational and interventional studies evaluating factors at the individual, familial, or environmental levels, for instance, size at birth, gestational age, breastfeeding, mode of conception, gestational diabetes, or smoking, were included. Quality was evaluated based on study methodological validity (adjusted Newcastle-Ottawa Scale if observational; Cochrane collaboration risk of bias tool if interventional) and CIMT measurement reliability. Estimates from bivariate or partial associations that were least adjusted for sex were used for pooling data across studies, when appropriate, using random-effects meta-analyses. The research protocol was published and registered on the International Prospective Register of Systematic Reviews (PROSPERO; CRD42017075169). Of 6,221 reports screened, 50 full-text articles from 36 studies (34 observational, 2 interventional) totaling 7,977 participants (0 to 18 years at CIMT assessment) were retained. Children born small for gestational age had increased CIMT (16 studies, 2,570 participants, pooled standardized mean difference (SMD): 0.40 (95% confidence interval (CI): 0.15 to 0.64, p: 0.001), I-2: 83%). When restricted to studies of higher quality of CIMT measurement, this relationship was stronger (3 studies, 461 participants, pooled SMD: 0.64 (95% CI: 0.09 to 1.19, p: 0.024), I-2: 86%). Only 1 study evaluating small size for gestational age was rated as high quality for all methodological domains. Children conceived through assisted reproductive technologies (ART) (3 studies, 323 participants, pooled SMD: 0.78 (95% CI: -0.20 to 1.75, p: 0.120), I-2: 94%) or exposed to maternal smoking during pregnancy (3 studies, 909 participants, pooled SMD: 0.12 (95% CI: -0.06 to 0.30, p: 0.205), I-2: 0%) had increased CIMT, but the imprecision around the estimates was high. None of the studies evaluating these 2 factors was rated as high quality for all methodological domains. Two studies evaluating the effect of nutritional interventions starting at birth did not show an effect on CIMT. Only 12 (33%) studies were at higher quality across all domains of CIMT reliability. The degree of confidence in results is limited by the low number of high-quality studies, the relatively small sample sizes, and the high between-study heterogeneity. Conclusions In our meta-analyses, we found several risk factors in the first 1,000 days of life that may be associated with increased CIMT during childhood. Small size for gestational age had the most consistent relationship with increased CIMT. The associations with conception through ART or with smoking during pregnancy were not statistically significant, with a high imprecision around the estimates. Due to the large uncertainty in effect sizes and the limited quality of CIMT measurements, further high-quality studies are needed to justify intervention for primordial prevention of cardiovascular disease (CVD). Author summary Why was this study done? Exposure to adverse experiences in the first 1,000 days of life, i.e., from conception to age 2 years, may determine adaptative changes in the blood vessel walls and increased carotid intima-media thickness (CIMT) in infants, children, and adolescents. This implies carotid arteries with thicker walls that may be due to changes in blood flow and pressure or other factors related to the process of atherosclerosis. What did the researchers do and find? We performed a systematic review of published studies with meta-analyses and included 36 studies, involving 7,977 participants between 0 and 18 years at CIMT assessment. Risk factors in the first 1,000 days of life, particularly poor fetal growth, are associated with increased CIMT in infants, children, and adolescents. There is scarce evidence from interventional studies beginning in the first 1,000 days, and none was shown to prevent or improve vascular remodeling in children. CIMT measurement protocols in children are heterogeneous and often poorly reported. What do these findings mean? From a public health perspective, acting early in life by preventing risk factors such as poor fetal growth could help maintain a low cardiovascular risk over the life course. Assessing vascular structure and function in children is important to better characterize lifetime risk trajectories and tailor primordial prevention of cardiovascular disease (CVD). Primordial prevention aims to prevent the development of risk factors instead of treating them. From a clinical standpoint, promotion of a healthy lifestyle is important at any age, and screening of postnatal cardiovascular risk factors, targeted at children exposed to risk factors in the first 1,000 days of life, may be warranted. A widely accepted standardized CIMT measurement protocol in children is needed.