Maternal and Fetal Folate, Vitamin B12, and Homocysteine Concentrations and Childhood Kidney Outcomes

Abstract

Background: Folate, vitamin B₁₂, and homocysteine concentrations during pregnancy are important factors for early development and may persistently influence kidney function in the offspring. We examined the associations of folate, vitamin B₁₂, and homocysteine concentrations during pregnancy with kidney outcomes in school-aged children.

Study design: Population-based prospective cohort study from fetal life onward.

Settings & participants: This study was performed among 4,226 pregnant women and their children.

Predictors: Folate, vitamin B₁₂, and homocysteine blood concentrations measured in early pregnancy (median gestational age, 13.2 [IQR, 12.2-14.8] weeks) and at birth (cord blood).

Outcomes & measurements: At the median age of 6.0 (IQR, 5.9-6.3) years, we measured combined kidney volume with ultrasound, estimated glomerular filtration rate based on creatinine (eGFR_cr) and cystatin C (eGFR_cys) concentrations, and microalbuminuria.

Results: We observed that higher maternal folate concentrations were associated with larger childhood combined kidney volume, whereas higher maternal vitamin B₁₂ concentrations were associated with higher childhood eGFR_cys (P for both <0.05). These associations were independent of homocysteine concentrations. Higher maternal homocysteine concentrations were associated with smaller combined kidney volume and lower childhood eGFR_cys (P for both < 0.05). The association of maternal homocysteine concentrations with childhood eGFR_cys was largely explained by combined kidney volume. Higher cord blood homocysteine concentrations were associated with larger combined kidney volume and lower eGFR_cys (P for both < 0.05). Folate, vitamin B₁₂, or homocysteine concentrations were not associated with microalbuminuria.

Limitations: Observational study, so causality cannot be established.

Conclusions: Our findings suggest that folate, vitamin B₁₂, and homocysteine concentrations during fetal life are associated with offspring kidney development. However, effect sizes are small. Further studies to replicate these findings and assess the causality and consequences for kidney health in later life are needed.

Keywords: Folate; epidemiology; estimated glomerular filtration rate (eGFR); fetal nutritional exposure; gestation; homocysteine; kidney development; kidney function; kidney volume; maternal nutrition; methyl donors; modifiable risk factor; nephrogenesis; pediatrics; pregnancy; vitamin B(12).

Figure 1. Folate, vitamin B₁₂ and homocysteine metabolism

Schematic representation of homocysteine metabolism. Folate and vitamin B₁₂ work closely together on homocysteine metabolism, handing off methyl groups to each other. TH-Folate is converted to 5,10-Methylene-TH-Folate which is further reduced to 5- Methyl-TH-Folate. With the demethylation of 5-Methyl-TH-Folate, the methyl group is donated into the methionine cycle. Vitamin B₁₂ is involved directly in the transfer of the methyl group to homocysteine, through methionine synthase. Methionine synthase is a vitamin B₁₂- dependent enzyme that catalyzes the formation of methionine from homocysteine The methionine cycle begins with homocysteine that accepts the methyl group from the folate pool through 5- Methyl-TH-Folate. Abbreviations: TH- Folate, Tetrahydro- folate.