Abstract
BACKGROUND: Inadequate provision of vitamin B(12) during pregnancy is associated with a number of adverse maternal and fetal outcomes. We set out to (1) suggest pregnancy-specific reference ranges for a range of biomarkers of vitamin B(12); (2) assess the temporal behaviors of these markers over the course of pregnancy; and (3) test whether any biomarkers, including the genetic marker HIBCH rs291466 strongly associated with MMA measured early in pregnancy could reliably and significantly predict future B(12) status within a healthy UK population of pregnant women. MATERIALS AND METHODS: We used existing biobank samples from the placebo arm of the UK Selenium in PRegnancy Intervention (SPRINT) study, to generate biochemical data for serum folate, B(12), holotranscobalamin (HoloTC), total homocysteine (tHcy), and MMA, calculate cB(12), and genotyped the polymorphism rs291466 in gene HIBCH on a total of n=114 women across trimesters 1-3 of their pregnancy. We performed a series of exploratory cross-sectional and longitudinal analyses to investigate levels at each trimester, suggest references ranges, evaluate changes and correlations between the B(12) biomarkers, and assess the predictive capabilities of each biomarker from 12-weeks to 35-weeks of gestation. RESULTS: Significant changes in all vitamin B(12) biomarker values were observed over the three trimesters (P < 0.05). Our study shows that cB(12) values were largely constant and stable throughout trimester 1 (T1) and T2 (i.e., up to week 20), but declined significantly in T3 (-66% | P < 0.001). Yet, cB(12) generally remained within the normal boundaries. We identified pregnancy and trimester-specific reference ranges for each biomarker at each trimester, notably for total serum B(12). This marker fell below the recommended cut-offs in 1/3 of the cohort at the third trimester, contrasting other markers (mostly normal). Our multivariate analyses indicated that none of the biomarkers could reliably and accurately predict any other biomarkers than themselves later in pregnancy. Yet, HoloTC seems to be a promising predictor within the limitations of our cohort, constituted of B(12)-replete individuals. Most notably, cB(12) did not significantly predict itself between trimesters. Finally, we show that the HIBCH variant has little predictive power for MMA or cB(12) as it does not explain the significant increase in MMA concentrations nor the decline of cB(12) throughout pregnancy. CONCLUSION: Trimester-specific reference ranges for biomarkers of vitamin B(12) in normal pregnancy are suggested. However, these biomarkers have limited predictive value in identifying mothers at elevated risk of vitamin B(12) insufficiency/deficiency during pregnancy.