Effect of antenatal magnesium sulphate on MRI biomarkers of white matter development at term equivalent age: The MagNUM Study

Abstract

Background: Magnesium sulphate given to women prior to very preterm birth protects the perinatal brain, so fewer babies die or develop cerebral palsy. How magnesium sulphate exerts these beneficial effects remains uncertain. The MagNUM Study aimed to assess the effect of exposure to antenatal magnesium sulphate on MRI measures of brain white matter microstructure at term equivalent age.

Methods: Nested cohort study within the Magnesium sulphate at 30 to <34 weeks' Gestational age Neuroprotection Trial (MAGENTA). Australian New Zealand Clinical Trials Registry ACTRN12611000491965. Mothers at risk of preterm birth at 30 to <34 weeks' gestation were randomised to receive either 4 g of magnesium sulphate heptahydrate [8 mmol magnesium ions], or saline placebo, when preterm birth was planned or expected within 24 h. Participating babies underwent diffusion tensor MRI at term equivalent age. The main outcomes were fractional anisotropy across the white matter tract skeleton compared using Tract-based Spatial Statistics (TBSS), with adjustment for postmenstrual age at birth and at MRI, and MRI site. Researchers and families were blind to treatment group allocation during data collection and analyses.

Findings: Of the 109 babies the demographics of the 49 babies exposed to magnesium sulphate were similar to the 60 babies exposed to placebo. In babies whose mothers were allocated to magnesium sulphate, fractional anisotropy was lower within the corticospinal tracts and corona radiata, the superior and inferior longitudinal fasciculi, and the inferior fronto-occipital fasciculi compared to babies whose mothers were allocated placebo (P < 0·05).

Interpretation: In babies born preterm after 30 weeks' gestation, antenatal magnesium sulphate exposure did not promote development of white matter microstructure in pathways affecting motor or cognitive function. This suggests that if the neuroprotective effect of magnesium sulphate treatment prior to preterm birth is confirmed at this gestation, the mechanisms are not related to accelerated white matter maturation inferred from fractional anisotropy.

Funding: This study was funded by a project grant from the Health Research Council of New Zealand (HRC 14/153).

Keywords: Antenatal magnesium sulphate; Brain development; Cerebral palsy; Diffusion tensor magnetic resonance imaging; Fetal neuroprotection; Preterm birth.

Figure 1

MagNUM Study recruitment and inclusion in Tract-Based Spatial Statistics (TBSS) analysis.

Figure 2

Tract-based spatial statistics comparing the brain white matter skeletons at term equivalent age of babies exposed in utero to magnesium sulphate or placebo Footnote: A group-specific template underlies each axial (top four rows) coronal (middle four rows) and sagittal (bottom four rows) slices, with the white matter tract skeleton shown in green. Regions where the magnesium sulphate group (n = 49) had a significantly lower diffusion metric than the placebo group (n = 60) are shown in red-yellow (family-wise error corrected, P < 0·05), while regions where the magnesium sulphate group had significantly higher measures than the placebo group are in blue.

Figure 3

Sensitivity and subgroup tract-based spatial statistics comparing the white matter skeletons of babies at term equivalent age of babies exposed in utero to magnesium sulphate or placebo Footnote: A group-specific template underlies each axial (right) coronal (middle) and sagittal (left) slices, with significant primary analysis differences between the magnesium and placebo groups indicated in green. Regions where babies who received magnesium sulphate had a significantly (family-wise error corrected, (P < 0·05)) lower FA (red-yellow), higher RD (blue) or higher MD (pink) than babies who received placebo are layered over the template. a: Babies whose mother received at least some of their allocated treatment; b: Babies born <34 weeks’ gestation; c: Babies who did not have bronchopulmonary dysplasia or necrotising enterocolitis; d: Babies who were exclusively fed breast milk at the time of MRI; e: Babies who were 32 to <34 weeks’ gestation at trial entry.