Evaluating the Diagnostic Value of a Combined Indicator of Vitamin B12 Status (cB12) Throughout Pregnancy

Abstract

BackgroundInadequate provision of vitamin B12 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 B12; (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 B12 status within a healthy UK population of pregnant women.Materials and MethodsWe used existing biobank samples from the placebo arm of the UK Selenium in PRegnancy Intervention (SPRINT) study, to generate biochemical data for serum folate, B12, holotranscobalamin (HoloTC), total homocysteine (tHcy), and MMA, calculate cB12, 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 B12 biomarkers, and assess the predictive capabilities of each biomarker from 12-weeks to 35-weeks of gestation.ResultsSignificant changes in all vitamin B12 biomarker values were observed over the three trimesters (P < 0.05). Our study shows that cB12 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, cB12 generally remained within the normal boundaries. We identified pregnancy and trimester-specific reference ranges for each biomarker at each trimester, notably for total serum B12. 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 B12-replete individuals. Most notably, cB12 did not significantly predict itself between trimesters. Finally, we show that the HIBCH variant has little predictive power for MMA or cB12 as it does not explain the significant increase in MMA concentrations nor the decline of cB12 throughout pregnancy.ConclusionTrimester-specific reference ranges for biomarkers of vitamin B12 in normal pregnancy are suggested. However, these biomarkers have limited predictive value in identifying mothers at elevated risk of vitamin B12 insufficiency/deficiency during pregnancy.