Folate, Vitamin B12, and Homocysteine Levels in South Asian Women with Growth-retarded Fetuses

Abstract

Animal studies have found that inadequate nutrition during pregnancy may lead to vascular dysfunction and hypertension in offspring. In humans, vascular (endothelial) dysfunction and hypertension are causally linked to elevated homocysteine (Hcy) levels. Abnormally high Hcy levels result in part from deficits in folic acid and vitamin B12, which are required to remethylate homocysteine to methionine. The investigators therefore speculated that altered maternal and fetal levels of folate, vitamin B12, or Hcy are associated with intrauterine growth restriction (IUGR) and hypertensive pregnancy complications. Participants were 128 pregnant women of low socioeconomic status living in Lahore, Pakistan. Fetal growth was monitored by ultrasound starting at 12 weeks gestation. IUGR was defined as lack of an 11% or greater increase in estimated fetal weight over a period of at least 15 days. Maternal and cord blood levels of folate and vitamin B12 were measured by chemiluminescent immunoassay and total Hcy (tHcy) by fluorescence polarization immunoassay. Fifteen of the 128 women had pregnancy-induced hypertension and 14 had preeclampsia; none had chronic hypertension. Forty-six fetuses were growth-restricted, whereas 52 deliveries were preterm (before 37 completed weeks of gestation). In univariate analysis, Hcy levels were significantly higher in women who developed hypertension, delivered an IUGR infant, or delivered preterm. On multivariate analysis, women with the highest quartile of tHcy had a 3.5-fold increased risk of hypertensive illness (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.4–8.6), and those with relatively high Hcy levels were at increased risk of preterm delivery (OR, 2.5; 95% CI, 1.1–6.2). The youngest women, less than 22 years of age, had the highest Hcy levels and the greatest risk of IUGR (OR, 2.9; 95% CI, 1.1–8.2) compared with older women, and the risk of IUGR was not altered by hypertension. Women with the highest folate levels had the lowest risk of IUGR (OR, 0.31; 95% CI, 0.10–0.84). Cord blood levels of both folate and vitamin B12 were approximately twice as high as were maternal levels, but there was no substantial difference in Hcy levels. Cord blood levels of all 3 substances correlated significantly with maternal blood levels for normal-birth-weight infants. However, cord blood folic acid levels from IUGR infants delivered at term were half those of normal-birth-weight infants and correlated inversely with cord blood Hcy levels. No outcomes could be related to cord blood levels of vitamin B12 or Hcy. Nearly a decade ago, the U.S. Food and Drug Administration required manufacturers to fortify enriched cereal grain products with 140 μg of folic acid per 100 g of product. The goal was to reduce the number of infants born with neural tube defects (NTDs). A recently published report by Grosse et al (Am J Public Health 2005;95:1917–1922) describes using both cost–benefit analysis (CBA) and cost-effectiveness analysis (CEA) to estimate the economic benefit of folic acid fortification intended to prevent NTD births. The base-case scenario assumed that there were no adverse effects from fortification, and that fortification costs were limited to fortificant and nutrition label changes. It also acknowledged the results of fortification to date by assuming that the reduction in NTD births would be twice that predicted when fortification was initiated, and that the per-birth cost of caring for an infant with NTD would be 1.7 times higher than predicted, in part because of inflation. The worst-case scenario assumed that fortification was responsible for only 80% of the observed reduction in NTDs, that annual fortification costs were twice what was calculated, and that fortification had some adverse effects such as an increased incidence of pernicious anemia. Applying both CBA and CEA, folic acid fortification was associated with an annual net economic benefit ranging from $312 million (worst-case scenario) to $422 million (base-case scenario). Estimated cost savings, the net reduction in direct costs, were in the range of $88 million to $145 million per year, respectively. Although the worst-case figures are substantially lower than the best-case estimates, they greatly exceed estimates that were made before fortification.