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

Abstract

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), I2: 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), I2: 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), I2: 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), I2: 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).

Fig 1. Flow diagram showing the study selection process.

CENTRAL, Cochrane Central Register of Controlled Trials; EMBASE, Excerpta Medica database; MEDLINE, Medical Literature Analysis and Retrieval System Online.

Fig 2. Association of small size for gestational age with CIMT in children.

SMD in CIMT between children born with a small size for gestational age (exposed) and those born with an appropriate size for gestational age (reference) in (A) all studies or (B) studies at higher CIMT reliability. Weights are from random-effects model. A positive SMD corresponds to a higher CIMT in the exposed as opposed to reference. CI, confidence interval; CIMT, carotid-intima media thickness; N, sample size; p, p-value; SMD, standardized mean difference.

Fig 3. Association of prematurity with CIMT in children.

SMD in CIMT between children born preterm (exposed) and those born at term (reference) in (A) all studies or (B) studies at higher CIMT reliability. Weights are from random-effects model. A positive SMD corresponds to a higher CIMT in the exposed as opposed to reference. CI, confidence interval; CIMT, carotid-intima media thickness; N, sample size; p, p-value; SMD, standardized mean difference.

Fig 4

Association of (A) ART conception, (B) maternal diabetes in pregnancy, and (C) maternal smoking in pregnancy with CIMT in children. SMD in CIMT between children: (A) conceived through ART (exposed) or naturally (reference); (B) exposed to maternal diabetes during pregnancy (exposed) or not exposed (reference); and (C) exposed to maternal smoking during pregnancy (exposed) or not exposed (reference). Weights are from random-effects model. A positive SMD corresponds to a higher CIMT in the exposed as opposed to reference. ART, assisted reproductive technologies; CI, confidence interval; CIMT, carotid-intima media thickness; N, sample size; p, p-value; SMD, standardized mean difference.