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

Abstract

Seizures are common in newborns after asphyxia at birth and are often refractory to anti-seizure agents. Magnesium sulphate (MgSO ) 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 MgSO 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 MgSO (n = 12, 160 mg bolus + 48 mg h 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 MgSO 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 MgSO -asphyxia group, although both sexes had fewer seizures than the saline-asphyxia group, the greatest effect of MgSO was on male fetuses, with reduced numbers of seizures (P < 0.001) and seizure burden (P < 0.005). Only 1 out of 6 MgSO males had seizures on the second day post-UCO compared to 5 out of 6 MgSO 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 MgSO may have utility in treating perinatal seizures and has sexually dimorphic effects.

Trends in sex-specific differences in outcomes in extreme preterms: progress or natural barriers?

“…Both animal and human data show that sex-based analysis will provide important insights about the differential response of boys and girls to treatment regimens. For example, in a preterm fetal sheep model of asphyxia, male fetuses given magnesium sulfate after umbilical cord occlusion showed a greater reduction in seizures than female fetuses 40. A similar analysis of the sexual dimorphic effect of magnesium sulfate in humans has not been done, but could lead to more precise therapy for fetuses expected to be born preterm 39 41.…”

The Effect of Size, Maturation, Global Asphyxia, Cerebral Ischemia, and Therapeutic Hypothermia on the Pharmacokinetics of High-Dose Recombinant Erythropoietin in Fetal Sheep

“…Romney-Suffolk cross fetal sheep were instrumented on gestation day 99 (preterm, n = 36) or at day 125 (near-term, n = 25) (full term 147 days). All the surgical procedures were performed using aseptic techniques, as previously described [7,[19][20][21]. Fetal instrumentation at both gestations included brachial artery catheters for blood pressure measurement and preductal blood sample collection, and brachial vein catheters for drug infusion.…”

“…Here, we report an analysis of pharmacokinetic models of combined first-order and mixed-order elimination, first-order and saturable EPO-R-mediated clearance and rEPO treatment-induced changes in EPO-R to describe rEPO elimination. We examined the effect of an increase in fetal size, maturation, exposure to global asphyxia, cerebral ischemia, therapeutic hypothermia and exogenous rEPO treatment on the pharmacokinetics of high-dose rEPO in well-established fetal sheep models [7,[19][20][21][22]. Finally, we compared the pharmacokinetics of high-dose rEPO in preterm fetal sheep given an i.v.…”

Effects of delayed intraventricular TLR7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep

“…On day 103-104 of gestation, animals were randomly assigned to either sham asphyxia (n = 8), asphyxia + vehicle (n = 7) or asphyxia + GDQ (n = 7) groups. Umbilical cord occlusion (UCO) was induced at 07.30 hours by rapid complete inflation of the umbilical cord occluder for 25 minutes or until blood pressure fell below 8 mmHg or there was fetal asystole 29,30 . Sham control animals received no occlusion.…”