Background. South Asia is experiencing the most dramatic rise in the prevalence of type 2 diabetes and hypertension in the world, yet nearly one in three babies are still born low birth weight (<2.5 kg). The objective of this thesis is to explore the developmental origins of health and disease in a rural South Asian setting, by examining the effects of maternal nutrition during pregnancy on growth, blood pressure, cholesterol, insulin resistance and the risk of metabolic syndrome in childhood.
Methods. In 1999-2001, pregnant women were enrolled in a community-based cluster randomized controlled trial of antenatal micronutrient supplements in the rural Sarlahi District of Nepal. Women received either vitamin A alone, as the control, or with (1) folic acid, (2) folic acid + iron, (3) folic acid + iron + zinc or (4) a multiple micronutrient supplement containing these plus 11 other nutrients. From 2006-2007, we conducted a series of follow-up visits with 3451 children born during this trial, at the age of ∼7 years, to examine the effect of supplementation on growth and body composition, blood pressure, cholesterol, markers of insulin resistance, and the overall risk of metabolic syndrome. A subset of these children (N=2834) were singletons weighed and measured within 72 hrs of birth, and whose data was analyzed to examine the associations between birth weight and maternal nutritional status in early pregnancy on these same outcome indicators.
Results. At age 7y, children were short and thin with a mean height for age z-score (HAZ) of -2.0 (0.9), weight for age z-score (WAZ) of -2.4 (1.1), and BMI for age z-score of -1.4 (1.0) compared to the CDC 2000 growth reference. There was a crude negative association between birth weight and systolic (β=-0.89 mm Hg/kg [SE: 0.4]; p=0.016) and diastolic blood pressure (-0.92 [0.4]; p=0.017), which remained significant after adjustment for confounders. Neither birth weight nor maternal BMI in the first trimester was associated with any markers of insulin resistance. Increasing birth weight was associated with a reduced risk of high triglycerides (≥150 mg/dl; OR: 0.58 per kg; 95% CI: 0.36, 0.91), but an increased risk of high BMI (> 85 th percentile; OR: 2.87; 95% CI: 2.00, 4.12) and no difference in risk of metabolic syndrome as a whole. Maternal BMI in early pregnancy was associated with an increased risk of high childhood BMI (OR: 1.30; 95% CI: 1.19, 1.41) and with an increasing risk of metabolic syndrome (OR: 1.20; 95% CI: 1.07, 1.35). Maternal supplementation with folic acid-iron-zinc resulted in a reduction in triceps (TSF: -0.23 mm; 95% CI: -0.43, -0.03) and subscapular skinfold thickness (-0.17 mm; 95% CI: -0.31, -0.06) relative to the control. There was a corresponding reduction in arm fat area in this group (-0.16 cm 2; -0.32, 0.01, p=0.07) and a reduced risk of high BMI≥85th percentile; OR: 0.63; 95% CI: 0.40, 1.00, p=0.050). Supplementation with folic acid-iron-zinc resulted in reductions in the risk of stunting (OR: 0.77; 95% CI: 0.60, 1.00). There were no differences between groups in mean blood pressure, cholesterol, or markers of insulin resistance. There was a reduced risk of metabolic syndrome in the folic acid-iron-zinc group (OR: 0.47; 95% CI: 0.22, 0.99; p=048), most likely due to the reduction in adiposity.
Conclusions. In this environment of chronic malnutrition, birth weight was inversely associated with blood pressure in 7 yr old children. Supplementation with folic acid-iron-zinc resulted in alterations in growth and body composition that could have long-term implications for future risk of disease. These children represent the leading edge of the nutrition transition in Nepal and it will be important to follow them as they age, given their poor start to life.