Maternal homocysteine in pregnancy and offspring birthweight: epidemiological associations and Mendelian randomization analysis

Background: disturbed one-carbon (1-C) metabolism in the mother is associated with poor fetal growth but causality of this relationship has not been established.Methods: we studied the association between maternal total homocysteine and offspring birthweight in the Pune Maternal Nutrition Study (PMNS, Pune, India) and Parthenon Cohort Study (Mysore, India). We tested for evidence of causality within a Mendelian randomization framework, using a methylenetetrahydrofolatereductase (MTHFR) gene variant rs1801133 (earlier known as 677C→T) by instrumental variable and triangulation analysis, separately and using meta-analysis.Results: median (IQR) homocysteine concentration and mean (SD) birthweight were 8.6 µmol/l (6.7,10.8) and 2642g (379) in the PMNS and 6.0 µmol/l (5.1,7.1) and 2871g (443) in the Parthenon study. Offspring birthweight was inversely related to maternal homocysteine concentration—PMNS: –22g/SD [95% confidence interval (CI): (–50, 5), adjusted for gestational age and offspring gender]; Parthenon: –57?g (–92, –21); meta-analysis: –40g (–62, –17)]. Maternal risk genotype at rs1801133 predicted higher homocysteine concentration [PMNS: 0.30 SD/allele (0.14, 0.46); Parthenon: 0.21 SD (0.02, 0.40); meta-analysis: 0.26 SD (0.14, 0.39)]; and lower birthweight [PMNS: –46g (–102, 11, adjusted for gestational age, offspring gender and rs1801133 genotype); Parthenon: –78g (–170, 15); meta-analysis: –61g (–111, –10)]. Instrumental variable and triangulation analysis supported a causal association between maternal homocysteine concentration and offspring birthweight.Conclusions: our findings suggest a causal role for maternal homocysteine (1-C metabolism) in fetal growth. Reducing maternal homocysteine concentrations may improve fetal growth