Discussion
insufficiency, metabolic insufficiency, deficiency/depletion
LATE PREGNANCY, RIBOFLAVIN DEFICIENCY, RECRUITMENT, EARLY PREGNANCY, VITAMIN B12 DEFICIENCY, SECONDARY, VITAMIN B6 DEFICIENCY, VITAMIN D DEFICIENCY
Among UK, Singapore, and New Zealand women attempting to become pregnant in this multicenter randomized controlled trial, significant proportions had marginal or low status of folate, riboflavin, vitamin B12, and vitamin D at recruitment preconception, and a high proportion developed markers of functional vitamin B6 deficiency in late pregnancy despite only a small proportion having a low vitamin B6 status preconception. Plasma concentrations for the above vitamins, related vitamers, and metabolic insufficiency markers showed differing patterns of change from preconception to pregnancy and 6 months postdelivery. In prespecified secondary analyses of the trial, a formulation enriched with micronutrients in amounts available in over-the-counter supplements commenced preconception and continued throughout pregnancy substantially increased plasma folate, riboflavin, and vitamins B6, B12, and D concentrations and reduced the prevalence of their deficiency/depletion markers before and during pregnancy, with a persisting benefit of higher plasma vitamin B12 to 6 months postdelivery.As routinely recommended for preconception and pregnancy, supplementation with 400 μg folic acid daily in both the control and intervention groups raised plasma folate by >1 SDS from baseline to early pregnancy and reduced the prevalence of marginal folate status from 28.1% at baseline to 1.0% in early pregnancy. Our findings show that even with 400 μg, the lowest commonly marketed dose, there are appreciable improvements in folate status after 1 month and continued improvement into pregnancy. Plasma homocysteine in the control group fell substantially from preconception baseline to early pregnancy and again from early to late pregnancy, with greater falls in plasma homocysteine in the intervention group taking a supplement containing other micronutrients. While some have proposed that vitamin B6, riboflavin, and zinc might reduce homocysteine, there are data pointing away from this [In the control group, plasma riboflavin and flavin mononucleotide showed modest falls from preconception to early pregnancy, and again from early to late pregnancy. We considered measuring the gold standard erythrocyte glutathione reductase activation coefficient as a specific riboflavin deficiency marker, but resource to support this could not be secured. Detailed studies have identified ≤26.5 nmol/L as the change-point of plasma riboflavin below which the erythrocyte glutathione reductase activation coefficient becomes elevated [Plasma pyridoxal 5-phosphate in the control group showed a modest fall from preconception to early pregnancy, but then a substantial fall from early to late pregnancy, accompanied by a sharp rise in plasma HK and cystathionine:cysteine ratios, reflecting impairment of vitamin B6–dependent pathways in late pregnancy. For vitamin B6, pyridoxal 5-phosphate is the most commonly used status marker [In the control group, plasma vitamin B12 showed modest falls from preconception to early pregnancy, and a larger fall from early to late pregnancy, accompanied by increases in the late pregnancy prevalences of vitamin B12 deficiency and depletion (11.1% and 55.2%, respectively) and a rise in plasma methylmalonic acid as a marker of vitamin B12 insufficiency; this is in keeping with previous reports of raised vitamin B12 deficiency markers in late pregnancy [Plasma 25-hydroxyvitamin D in the control group taking a supplement without vitamin D was remarkably unchanged from preconception baseline to early pregnancy, then increased modestly between early and late pregnancy, with high prevalences of vitamin D deficiency and insufficiency at baseline preconception (47.7% and 85.7%, respectively) and through pregnancy. Supplementation with 10 μg of vitamin D in the intervention group led to progressive increases in plasma 25-hydroxyvitamin D and a substantial reduction in the prevalences of vitamin D deficiency and insufficiency during pregnancy (e.g., 8.5% and 27.3% in late pregnancy, respectively, versus 35.1% and 64.6% in the control group). The dose of vitamin D recommended for routine use in pregnancy varies internationally, with some advocating 100 μg daily or higher [The finding of significant prevalences of vitamin insufficiencies in women living in high-income countries who are attempting to become pregnant is a serious concern. This is particularly the case given increasing advocacy to reduce meat and dairy intakes to achieve “net-zero” carbon emissions, as these foods are micronutrient dense and support nutritional adequacy [Local policy in high- and low-income settings can introduce the investigated supplement amounts as the amounts incorporated into the intervention supplement are available in over-the-counter multivitamin and single-vitamin supplements. As such, the effects we report on vitamin status before and during pregnancy are generalizable and fill an important gap in the literature. With the supplement used in our trial, some participants nonetheless had persisting evidence of low or marginal vitamin status, and our findings point to a need to build an evidence base to inform food fortification and biofortification policymaking beyond the current principal focus on folic acid for prevention of neural tube defects.To date, changes in vitamin status from preconception to early and late pregnancy and postpartum have largely been inferred from cross-sectional data, with lower concentrations during pregnancy often ascribed to plasma volume expansion [