The neuroprotective benefit of antenatal MgSO4 for preterm infants is currently attributed to the magnesium, though mechanisms are putative at best. However, the potential contribution of sulphate has not been considered. We propose sulphate deficiency in preterm babies is detrimental to neurodevelopment. Our data positively correlate antenatal MgSO4 administration with neonatal plasma sulphate levels. However, some babies become sulphate deficient even though their mothers received MgSO4 therapy. These findings suggest that sulphate levels in the neonate vary not only due to MgSO4 exposure, but also to genetic factors that limit sulphate supply from mother to infant.
We recruited 36 very preterm infants (24-31 wk gestation) and their mothers, and sequenced the genes that are important for placental sulphate transfer (SLC13A4) and maintenance of maternal circulating sulphate levels via the renal sulfate transporters, SLC13A1 and SLC26A1. To determine whether genetic defects can explain low blood sulphate levels, we used ion chromatography to measure blood sulphate levels in the preterm infants at 3 days of age.
We identified a total of 9 variants that change amino acid sequences of SLC13A4, SLC13A1 and SLC26A1, including: 2 previously characterised loss-of-function variants (N174S and R12X) in SLC13A1; 6 variants in SLC26A1 (Q556R, G368S, L348P, R340C, A277T, A272E); and one variant in SLC13A4 (P451S). The L348P and P451S variants change amino acids in SLC26A1 and SLC13A4, respectively, which are highly conserved across species. We show a trend for decreased (approximately 30%, P=0.0511) plasma sulphate level in infants whose mothers have variants (N174S, R12X and L348P) in the renal SLC13A1 and SLC26A1 genes, and when carrying P451S in the placental SLC13A4 gene.
This is the first study to assess genetic variation in maternal kidney sulphate reabsorption and placental sulphate transport, which may explain why some preterm infants have low blood sulphate levels despite antenatal MgSO4 administration.