In a Rodent Model, Low-Dose Maternal Magnesium Sulfate Achieves Comparable Neuroinflammatory Attenuation to Higher Dose.

Abstract

Antenatal magnesium sulfate (Mg) is recommended for fetal neuroprotection in preterm birth, yet optimal dosing remains uncertain. The American College of Obstetricians and Gynecologists (ACOG), jointly with the Society for Maternal-Fetal Medicine (SMFM), endorses three dosing regimens with up to sevenfold variation in cumulative dose (i.e., 4g, 10.5g, or 31.5g). Maternal-fetal inflammation has been associated with fetal brain injury and adverse neurodevelopmental outcomes. Emerging evidence suggests a dose-dependent Mg effect, where low doses support neuronal survival, while higher doses may adversely induce neuronal apoptosis and neurodegeneration. This study aimed to compare the effects of low- and high-dose maternal MgSO₄ on fetal neuroinflammation in an established animal model of maternal inflammation. Pregnant Sprague-Dawley rats (n = 30) on gestational day 20 received intraperitoneal injections of lipopolysaccharide (LPS, 500 μg/kg) a component of gram-negative bacterial membranes used to model intrauterine infection or saline. Dams were then randomized to receive subcutaneous treatment with saline, low-dose Mg (150 mg/kg loading dose), or a high-dose protocol (150 mg/kg loading dose followed by 15 mg/kg every 20 minutes for 2 hours before and after the injection). The primary endpoint was fetal brain pro-inflammatory cytokine expression (IL-6 and TNF-α). Fetal brains and placentas were collected and assigned to one of six treatment groups. Tissues were analyzed for inflammatory cytokines (Western blot), and maternal/fetal serum was analyzed for Mg levels and cytokine concentrations (ELISA). Maternal and fetal serum Mg levels were lowest in the saline control groups, increased with low-dose Mg, and were highest with high-dose Mg, confirming dose-dependent transplacental transfer. Fetal brain inflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), were significantly elevated following maternal inflammation compared to saline controls (IL-6: 2.06±0.05 vs. 0.75±0.12U; TNF-α: 2.11±0.04 vs. 0.76±0.12U; P < 0.05). Both low- and high-dose Mg significantly reduced fetal brain cytokine levels to near baseline (Low Mg: IL-6 0.71±0.04U, TNF-α 0.75±0.13U; High Mg: IL-6 0.73±0.26U, TNF-α 0.74±0.33U; P < 0.05), with no significant difference between the two Mg groups. Comparable cytokine reduction was observed in placental tissue. In this experimental model, low-dose maternal Mg was as effective as a higher-dose regimen in attenuating fetal brain and placental pro-inflammatory cytokine expression following LPS-induced maternal inflammation. These findings suggest that a reduced Mg exposure, equivalent to a 4g loading dose in clinical practice, may be sufficient for fetal neuroprotection, and support the need for prospective clinical studies comparing reduced-duration Mg protocols.