Early life programming of cardiometabolic disease: the role of prenatal zinc, intrauterine growth, and the development of the fetal autonomic nervous system
Mispireta, Monica Liliana
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Background: Cardiovascular disease (CVD) and type 2 diabetes mellitus (DM) are major causes of mortality and disease burden among developing countries, yet maternal and child undernutrition are also still of great concern. The objective of this dissertation is to evaluate whether intrauterine growth, prenatal zinc, and the development of the fetal autonomic nervous system influence the risk of long-term health outcomes with emphasis on cardiometabolic disease. Methods: Data of pregnant women taking part in a maternal zinc supplementation trial in Lima, Peru between 1998 and 2000, and a follow-up of their offspring when they were approximately 4.5 years of age were used. A total of 242 women were randomized to receiving an oral supplement containing 60 mg iron (ferrous sulfate) and 250 µg folic acid, with or without 25 mg of zinc (zinc sulfate) daily throughout pregnancy. The health and nutritional status of the mother were assessed at enrollment (10-16 weeks of gestation), and again at 28 and 36 weeks. Fetal growth and neurobehavioral development (heart rate and movement patterns) were evaluated using ultrasound and electronic fetal monitoring at 20, 24, 28, 32, 36, and 38 weeks, respectively. In 2003, follow-up assessments were conducted with 184 children born during this trial, at the age of 4.5 years, to evaluate the effect of prenatal zinc on health, nutritional and developmental outcomes, including cardiorespiratory monitoring. In 2011, markers of cardiometabolic risk (lipid profile and insulin resistance) were measured in cryopreserved plasma samples collected from the children as part of the follow-up. Results: At 4.5 years, on average children were shorter (height for age Z-score = -0.85, SD = 0.79) and heavier (BMI for age Z-score = 0.77, SD = 0.95) than children of their same sex and age, when using the WHO growth standards. After adjusting for prenatal zinc supplement, gestational age at delivery and selected maternal characteristics, estimated fetal weight (EFW) was positively associated (P<0.05) with child height, weight, head circumference, fat mass index, sum of 4 skinfolds, and waist circumference in males and females. Relations between EFW and child BMI and fat-free mass index were also positive, but were statistically significant only among females. EFW was inversely associated with the ratio of subscapular/triceps skinfolds, but this association was statistically significant only among males. All associations tend to be strongest at 32 weeks and effect sizes correspond generally to moderate relationships (~0.3 SD). In general, associations of EFW with measures of child size were stronger for males, whereas associations between EFW and measures of child body composition were stronger for females. Similar associations were observed for weight at birth. The direction of the associations between individual fetal proportions (head circumference – HC, abdominal circumference – AC, or femur diaphysis length – FL) and measures of child size and body composition were similar. Prenatal zinc supplementation was not associated with an increased risk of the metabolic syndrome or any of its individual components at 4.5 years. Fetal heart rate (FHR) was inversely associated with child heart period (HP, the distance in milliseconds between two heart beats), all measures of cardiac variability, and vagal tone (V, a measure of parasympathetic control) at 4.5 years. Two measures of cardiac variability in the fetal period, the range of HR, and the number of episodic accelerations of heart rate, were also significantly associated with childhood measures of heart period and variability. Conclusions: Overall, the findings of the present study support the hypothesis that intrauterine growth and development have an association with anthropometric and cardiometabolic parameters in early childhood that are known to be precursors of cardiometabolic disease later in adulthood; however, zinc supplementation received by the pregnant mother did not appear to influence the presence of cardiometabolic conditions in early childhood.