Time and sex dependent effects of magnesium sulphate on post-asphyxial seizures in preterm fetal sheep

Abstract

Key points: We evaluated the effect of magnesium sulphate (MgSO₄ ) on seizures induced by asphyxia in preterm fetal sheep. MgSO₄ did not prevent seizures, but significantly reduced the total duration, number of seizures, seizure amplitude and average seizure burden. Saline-asphyxia male fetuses had significantly more seizures than female fetuses, but male fetuses showed significantly greater reduction in seizures during MgSO₄ infusion than female fetuses. A circadian profile of seizure activity was observed in all fetuses, with peak seizures seen around 04.00-06.00 h on the first and second days after the end of asphyxia. This study is the first to demonstrate that MgSO₄ has utility as an anti-seizure agent after hypoxia-ischaemia. More information is needed about the mechanisms mediating the effect of MgSO₄ on seizures and sexual dimorphism, and the influence of circadian rhythms on seizure expression.

Abstract: Seizures are common in newborns after asphyxia at birth and are often refractory to anti-seizure agents. Magnesium sulphate (MgSO₄ ) has anticonvulsant effects and is increasingly given to women in preterm labour for potential neuroprotection. There is limited information on its effects on perinatal seizures. We examined the hypothesis that MgSO₄ infusion would reduce fetal seizures after asphyxia in utero. Preterm fetal sheep at 0.7 gestation (104 days, term = 147 days) were given intravenous infusions of either saline (n = 14) or MgSO₄ (n = 12, 160 mg bolus + 48 mg h^-1 infusion over 48 h). Fetuses underwent umbilical cord occlusion (UCO) for 25 min, 24 h after the start of infusion. The start time for seizures did not differ between groups, but MgSO₄ significantly reduced the total number of seizures (P < 0.001), peak seizure amplitude (P < 0.05) and seizure burden (P < 0.005). Within the saline-asphyxia group, male fetuses had significantly more seizures than females (P < 0.05). Within the MgSO₄ -asphyxia group, although both sexes had fewer seizures than the saline-asphyxia group, the greatest effect of MgSO₄ was on male fetuses, with reduced numbers of seizures (P < 0.001) and seizure burden (P < 0.005). Only 1 out of 6 MgSO₄ males had seizures on the second day post-UCO compared to 5 out of 6 MgSO₄ female fetuses (P = 0.08). Finally, seizures showed a circadian profile with peak seizures between 04.00 and 06.00 h on the first and second day post-UCO. Collectively, these results suggest that MgSO₄ may have utility in treating perinatal seizures and has sexually dimorphic effects.

Keywords: asphyxia; magnesium sulphate; seizures.

Figure 1. The onset time of seizures after the end of umbilical cord occlusion (A) and the total time spent seizing from first to last seizure (B) in saline‐asphyxia (open circles) and MgSO₄‐asphyxia (filled circles) treated fetuses

Data are median (interquartile ranges). NS, not significant.

Figure 2. The total number of seizures (A), peak seizure amplitude (B) and seizure burden (C) in saline‐asphyxia (open circles) and MgSO₄‐asphyxia (filled circles) treated fetuses

Data are median (interquartile ranges).

Figure 3. Start time of seizures after the end of umbilical cord occlusion (A) and the total time spent making seizures (B) in female and male saline‐asphyxia fetuses (open and filled circles), and female and male MgSO₄‐asphyxia fetuses (open and filled squares)

Data are median (interquartile ranges).

Figure 4. The total number of seizures (A), peak seizure amplitude (B) and seizure burden (C) in female and male saline‐asphyxia fetuses (open and filled circles), and female and male MgSO₄‐asphyxia fetuses (open and filled squares)

Data are median (interquartile ranges).

Figure 5. Time sequence of changes in numbers of seizures (A), peak seizure amplitude (B) and seizure burden (C) in saline‐asphyxia (open bars) and MgSO₄‐asphyxia (filled bars) fetuses

Data are mean ± SEM.

Figure 6. Time sequence of changes in number of seizures (A), peak seizure amplitude (B) and seizure burden (C) in female saline‐asphyxia fetuses (open bars) and female MgSO₄‐asphyxia fetuses (filled bars)

Data are mean ± SEM.

Figure 7. Time sequence of changes in number of seizures (A), peak seizure amplitude (B) and seizure burden (C) in male saline‐asphyxia fetuses (open bars) and male MgSO₄‐asphyxia fetuses (filled bars)

Data are mean ± SEM.