Magnesium Sulfate for Brain Protection in Neonatal Encephalopathy: A Systematic Review

Magnesium Sulfate for Brain Protection in Neonatal Encephalopathy: A Systematic Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Magnesium Sulfate for Brain Protection in Neonatal Encephalopathy: A Systematic Review Joseph Mendlovic, Francis Mimouni, Yuval Yuval, Iris Arad This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9362928/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Objective: To evaluate the safety and efficacy of postnatal magnesium sulfate (MgSO₄) for neuroprotection in neonates with neonatal encephalopathy (NE). Study design: Systematic review and meta-analysis of controlled clinical trials assessing MgSO₄ administered within 12 hours of birth in term or near-term infants with NE. Databases searched included MEDLINE, Embase, and Cochrane sources. Results: Twenty-four trials were included. MgSO₄ was consistently safe, with no significant adverse hemodynamic or respiratory effects. Meta-analyses demonstrated improved short-term outcomes, including reduced seizure occurrence, improved neurological status at discharge, and earlier establishment of feeding. No significant reduction in mortality was observed. Evidence regarding long-term neurodevelopmental outcomes was extremely limited. Data on MgSO₄ use alongside therapeutic hypothermia were scarce and inconclusive. Conclusion: Postnatal MgSO₄ is safe and associated with improved short-term clinical outcomes in neonates with NE. However, absence of long-term benefit and limited evidence in the era of therapeutic hypothermia preclude routine clinical use. Health sciences/Diseases/Neurological disorders/Paediatric neurological disorders Health sciences/Health care/Paediatrics magnesium sulfate neonatal encephalopathy neuroprotection hypoxic-ischemic encephalopathy neonatal hypoxia Figures Figure 1 Figure 2 INTRODUCTION Neonatal encephalopathy (NE), most commonly resulting from intrapartum hypoxia-ischemia, remains a major cause of neonatal mortality and long-term neurodevelopmental impairment worldwide. Despite advances in perinatal care, survivors of moderate-to-severe hypoxic-ischemic encephalopathy (HIE) remain at high risk for epilepsy, cerebral palsy, cognitive impairment, and behavioral disorders 1 , 2 . Therapeutic hypothermia is the standard neuroprotective intervention for eligible term and near-term infants and has been shown to reduce death and disability. However, a substantial proportion of treated infants continue to experience adverse outcomes, highlighting the need for additional neuroprotective strategies 1 , 2 . Magnesium sulfate (MgSO₄) is a biologically plausible candidate for neuroprotection in NE. Its mechanisms of action target key components of the hypoxic-ischemic injury cascade, including excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptor activation, intracellular calcium influx, oxidative stress, and inflammation 3 . By acting as a physiological NMDA receptor antagonist, MgSO₄ modulates calcium entry and downstream cellular injury pathways. It may also stabilize cellular membranes and influence cerebral vascular tone, further supporting its potential neuroprotective role 3 . These properties, combined with its wide availability and established clinical use, have driven interest in MgSO₄ as a postnatal intervention in neonates with NE. Clinical interest in MgSO₄ has also been informed by strong evidence supporting its antenatal use for fetal neuroprotection in threatened preterm birth 3 , 4 . Large randomized trials and meta-analyses have demonstrated a reduction in the risk of cerebral palsy among preterm infants exposed to antenatal MgSO₄, leading to widespread adoption in clinical practice. Although the mechanisms and clinical contexts differ between preterm brain injury and term HIE, these findings provide a rationale for evaluating MgSO₄ as a postnatal neuroprotective agent. Over the past two decades, multiple clinical studies have evaluated postnatal MgSO₄ administration in term and near-term neonates with perinatal asphyxia or NE. These studies have used a range of clinical and surrogate outcomes, including seizure burden, neurological examination at discharge, neuroimaging findings, and feeding ability. Early trials suggested potential short-term benefits without significant safety concerns. However, most studies were small, with heterogeneous inclusion criteria, dosing regimens, and outcome definitions. With the widespread adoption of therapeutic hypothermia, the role of MgSO₄ requires re-evaluation in the context of modern neonatal care. Combination neuroprotection is conceptually attractive, as hypothermia targets multiple downstream injury pathways and may complement agents that primarily modulate excitotoxicity. At the same time, combination therapy introduces potential interactions and increases the evidentiary threshold for demonstrating additional benefit. Existing studies of MgSO₄ in the era of hypothermia are limited, and prior meta-analyses have not demonstrated clear improvements in clinically meaningful outcomes such as death or long-term disability 4 . This systematic review aims to provide a comprehensive and updated synthesis of the evidence on postnatal MgSO₄ administration in neonates at risk of hypoxic-ischemic brain injury. We focus on clinically relevant outcomes, including mortality, seizures, neurological status, and neurodevelopment when available, as well as safety and feasibility considerations in both pre-hypothermia and contemporary clinical settings. METHODS Search strategy This systematic review adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines and follows a protocol similar to that used in our previous work 8 . Parallel searches were conducted in MEDLINE, Embase, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials. We used broad search terms combined with thesaurus explode functions to maximize sensitivity. To improve specificity, both built-in filters and additional keywords were applied. Two search strategies were used. In the first, the terms “magnesium AND (neonate OR newborn OR infant)” were applied with language restricted to English. In the second, the term “magnesium” was used with filters for English language and age (infant, newborn). Reference lists of all included studies were manually screened to identify additional eligible articles. Data collection All studies including neonates with encephalopathy or asphyxia receiving postnatal MgSO₄ and comparing them with appropriate controls were retained for full-text review. Our primary objective was to evaluate all studies for new evidence on MgSO₄ administration after HIE for the purpose of brain protection. We included in the final analyses only trials that included an appropriate control group. Titles and abstracts of records identified by the search were reviewed by 2 authors (YD and FBM) and either "included" or "excluded" as full-text articles. An Excel data collection form was used to extract and record information on design, methods and participants from each study. Disagreements were resolved through consensus among reviewers. Statistical analysis Analyses were performed using Review Manager (RevMan), version 5.4 (Cochrane Collaboration, Copenhagen, Denmark), for primary meta-analyses and forest plot generation, with supplementary analyses and graphical assessments conducted using Stata, version 16 (StataCorp, College Station, TX, USA). Data management and preliminary checks were conducted using Microsoft Excel. Meta-analyses were pre-specified for randomized controlled trials evaluating postnatal MgSO₄ administration in term neonates with HIE. All studies were first analyzed and described qualitatively. Quantitative synthesis was restricted to studies with comparable eligibility criteria, MgSO₄ dosing and administration protocols, and sufficiently similar outcome definitions. Because outcomes were inconsistently reported across trials, separate meta-analyses were conducted for each outcome using only studies reporting that specific outcome. The primary outcome was in-hospital or pre-discharge mortality. Secondary outcomes included the occurrence of any clinical seizures, abnormal neurological status at discharge, and failure to establish oral or enteral feeding by discharge. Electroencephalographic or amplitude-integrated EEG findings, neuroimaging abnormalities, biochemical markers of brain injury, and long-term neurodevelopmental outcomes were excluded from quantitative analysis because of heterogeneity in biomarker type, biological matrix, sampling schedule, and clinical context, precluding any meaningful quantitative synthesis. These studies were therefore only analyzed and summarized qualitatively. All outcomes were dichotomous and were analyzed as risk ratios (RRs) with corresponding 95% confidence intervals (CIs). Meta-analyses were performed using a random-effects model based on the DerSimonian-Laird method, to account for anticipated clinical and methodological heterogeneity between studies. Statistical heterogeneity was assessed using the I² statistic and between-study variance (τ²). Forest plots were generated on a logarithmic scale, with RR values below 1 indicating a direction of effect favoring MgSO₄. Statistical significance was defined as a two-sided p value < 0.05. Sensitivity Analysis Formal sensitivity analyses were not performed because of the limited number of studies available per outcome and incomplete reporting of key methodological variables. To reduce potential bias, pooling was restricted to trials with broadly comparable designs and MgSO₄ administration protocols, and outcomes were combined only when definitions and timing were sufficiently aligned. Consistency of effect estimates across studies was assessed qualitatively through visual inspection of forest plots. RESULTS Our search retrieved 7 Randomized Controlled Trials (RCTs), 5 systematic reviews, and 1 narrative review. The 5 systematic reviews and meta-analyses of Tagin (2013) 9 , Gowda (2023) 10 , Fei (2024) 11 , Shepherd (2024) 4 and Yang (2024) 12 allowed to retrieve 17 additional RCTs (Fig. 1). We identified and analyzed 24 RCTs. They are described in a qualitative approach, and meta-analyses, whenever possible, are then performed, when similar MgSO₄ administration protocols are used. Groenendaal et al. (2002) 5 conducted in the Netherlands a double-blind, randomized, placebo-controlled pilot study in 22 term neonates with perinatal asphyxia (defined as: ≥3 of: fetal hypoxia signs, umbilical pH < 7.10, resuscitation need, Apgar ≤ 5 at 10 min, or intermittent positive pressure ventilation at 10 min), to assess the effect of postnatal MgSO₄ on cerebral electrophysiological recovery using amplitude-integrated electroencephalography (aEEG). Infants were enrolled within 2–3 h of birth and randomized to MgSO₄ (n = 8) or placebo (n = 14). MgSO₄ was administered shortly after admission (≈ 250 mg/kg), with additional doses at 24 and 48 h, achieving a mean serum MgSO₄ concentration of ≈ 2.5 mmol/L. The primary outcome was change in aEEG background pattern over the first 24 h; secondary outcomes included seizures and neurodevelopment up to 24 months. MgSO₄ did not improve aEEG background activity. Instead, transient suppression of aEEG between 3 and 12 h of life occurred more frequently in the MgSO₄ group than in controls (6/8 vs 3/14, p < 0.05), with no differences thereafter. There were no significant differences in seizure burden, antiepileptic treatment, mortality, or long-term neurodevelopmental outcomes. Postnatal MgSO₄ provided no evidence of neuroprotective benefit and might be associated with transient cerebral electrical suppression, leading to early termination of the trial. No clinical neurodevelopmental follow-up was performed in this study. Ichiba et al (2002) 6 conducted in Japan a multicenter randomized controlled trial to evaluate whether postnatal MgSO₄ infusion (250 mg/kg/day for three days) is safe and improves outcomes in term infants with severe birth asphyxia (defined as: 5-min Apgar ≤ 7 and either failure to initiate spontaneous respiration at 10 min or clinical seizures within 24h). The trial was sufficiently powered to detect a 50% reduction in adverse outcomes. Baseline characteristics and HIE severity were comparable between groups. In terms of safety, cardiovascular parameters (blood pressure, heart rate, respiratory rate) remained similar between groups. In terms of efficacy, MgSO₄ therapy did not reduce seizure duration or the need for assisted ventilation. However, survival with normal cranial CT, normal EEG, and successful oral feeding by 14 days were significantly more frequent in the MgSO₄ group than in controls (12/17 vs. 5/16, p = 0.04). Overall, postnatal MgSO₄ at this dosing regimen is safe and may improve short-term neurological and feeding outcomes. No clinical neurodevelopmental follow-up was performed in this study. Gathwala et al (2006) 13 conducted in India a randomized controlled study in 40 term neonates with severe birth asphyxia (defined as: 1-min Apgar < 3 and 5-min Apgar < 6) to evaluate the safety and serum MgSO₄ concentration achieved with postnatal MgSO₄ administration. Infants were randomized to receive MgSO₄ (n = 20) or standard care alone (n = 20). The intervention consisted of an intravenous loading dose of 250 mg/kg within 30 min of birth, followed by two doses of 125 mg/kg at 24 and 48 h. Primary outcomes included serial serum MgSO₄ concentrations and continuous monitoring of cardiorespiratory and hemodynamic parameters. MgSO₄-treated infants achieved significantly higher serum MgSO₄ concentration at all post-treatment time points compared with controls (p < 0.001), with concentrations ranging from 1.47 to 1.92 mmol/L, within the proposed neuroprotective range. No significant adverse effects were observed on heart rate, respiratory rate, oxygen saturation, or mean arterial pressure. Overall, this MgSO₄ regimen was safe, well tolerated, and capable of maintaining sustained serum MgSO₄ concentrations. No clinical neurodevelopmental follow-up was performed in this study. Khashaba et al. (2006) 14 conducted in Egypt a double-blind randomized controlled trial in 47 term neonates with perinatal asphyxia (defined as: 5-min Apgar score ≤ 3 and/or delayed first breath > 10 minutes after birth) to investigate cerebrospinal fluid (CSF) excitatory amino acid dynamics and the effect of postnatal MgSO₄. Infants were randomized within the first 24 hours of life to receive an i.v. 10% solution of MgSO₄ at a dose of 250 mg/kg administered over 10 minutes (n = 23) or an equal volume of isotonic saline (0.9%) as placebo (n = 24). CSF glutamate and aspartate concentrations were measured at baseline and at 72 hours, with concurrent clinical and neurological monitoring. Higher baseline CSF excitatory amino acid levels correlated significantly with increasing HIE severity, and concentrations declined over time in both groups. This study demonstrated that aspartate concentrations did not change significantly over time in either the placebo group (− 0.45 ± 1.96 µMol/L, p = 0.34) or the MgSO₄ group (− 0.70 ± 3.19 µMol/L, p = 0.37). There were no between-group differences in aspartate levels at baseline (3.52 ± 2.40 vs. 3.92 ± 2.59 µMol/L, p = 0.49) or at 72 hours (2.79 ± 1.24 vs. 3.05 ± 2.48 µMol/L, p = 0.92). Overall, postnatal administration of MgSO₄ had no effect on CSF aspartate concentrations compared with placebo, did not modify excitotoxic biomarker profiles in neonatal HIE, and provided no biochemical evidence of neuroprotection when administered after birth. No clinical neurodevelopmental follow-up was performed in this study. Bhat et al (2009) 7 conducted in India a randomized, placebo-controlled clinical trial of 40 term neonates with severe perinatal asphyxia and moderate to severe HIE (defined as 3 of 4: fetal distress, ventilation ≥ 2 min, 5-min Apgar ≤ 6, or pH ≤ 7/base deficit ≥ 15 within 1h), treated with 3 doses of MgSO₄ infusion at 250 mg/kg per dose, 24 hours apart, or normal saline (placebo group) within hours of birth. At discharge, 22% of infants in the treatment group had neurologic abnormalities, compared with 56% (P < 0.04) of infants in the placebo group. Infants in the treatment group were more likely to be receiving oral feedings (sucking) at discharge than were those in the placebo group (77% vs 37%, P < 0.02). No clinical neurodevelopmental follow-up was performed in this study. Gathwala et al (2010) 15 extended their investigation from safety to clinical efficacy in a subsequent randomized controlled trial, conducted in India, comparing postnatal intravenous MgSO₄ (250 mg/kg within 30 minutes of birth, followed by 125 mg/kg at 24 and 48 hours) versus standard care in 40 term neonates with severe birth asphyxia (defined as: 1-min Apgar score ≤ 3 AND 5-min Apgar score ≤ 6), 20 in each group. Of these, 4 died and 16 continued follow-up assessment until the age of 6 months. Cranial CT and EEG were assessed by blinded evaluators, and surviving infants underwent neurodevelopmental assessment at 6 months using the Denver II screening test. Magnesium Sulfate was well tolerated and was associated with fewer EEG and CT abnormalities and more favorable short-term neurodevelopmental outcomes compared with controls; however, these differences were not statistically significant, suggesting a possible neuroprotective effect. No clinical neurodevelopmental follow-up was performed in this study. Hossain et al. (2013) 16 conducted in Bangladesh a randomized, single-blinded, placebo-controlled clinical trial in 50 term neonates aged < 12 hours with moderate or severe HIE following perinatal asphyxia (defined as history of perinatal asphyxia and one of: 5-min Apgar ≤ 6, moderate/severe HIE, or seizures within 12h). Infants were randomized to receive either three intravenous doses of MgSO₄ at 250 mg/kg per dose, infused over 1 hour at 24-hour intervals, or three equal-volume doses of normal saline, in addition to standardized supportive care. No therapeutic hypothermia was administered. Serum MgSO₄ concentrations were measured at admission and at 48 hours, and infants were monitored for cardiorespiratory stability, neurological status, feeding ability, EEG abnormalities, and mortality. MgSO₄-treated infants achieved significantly higher serum MgSO₄ concentrations within the proposed neuroprotective range without significant hemodynamic or respiratory adverse effects. Compared with controls, the MgSO₄ group had significantly fewer neurological abnormalities at discharge (26% vs. 61%), higher rates of successful oral feeding by sucking (78% vs. 44%), and a greater proportion of good short-term outcomes (composite of normal neurological examination and oral feeding (60% vs. 32%), while EEG abnormalities and mortality (26%) did not differ significantly between groups. No clinical neurodevelopmental follow-up was performed in this study. Dixon et al (2015) 17 presented a narrative, mechanism-informed review of MgSO₄ in neonatal HIE (based upon acute intrapartum events causing moderate/severe encephalopathy, metabolic acidosis, and absence of other palsy causes), integrating preclinical mechanistic data and translational animal studies with available clinical evidence. In the clinical domain, his conclusions rely primarily on the systematic review by Tagin et al., rather than on individual randomized controlled trials. Based on this synthesis, Dixon concluded that despite strong biological plausibility and signals of short-term improvement without excess adverse effects, there is insufficient evidence that postnatal MgSO₄ reduces mortality or moderate-to-severe neurodevelopmental disability, and that inconsistent results, methodological heterogeneity, and concerns regarding temperature control and mortality trends warrant further adequately powered, rigorously controlled trials before clinical efficacy can be established. No clinical neurodevelopmental follow-up was performed in this study. Mahmood et al. (2015) 18 conducted in Pakistan a randomized blinded controlled trial including 70 term neonates admitted within 6 hours of birth with moderate-to-severe hypoxic-ischemic encephalopathy (defined by: history of fetal distress, immediate ventilation ≥ 2 min, 5-min Apgar < 6, and pH 15). Infants were randomized to receive intravenous MgSO₄ at a dose of 250 mg/kg (1 mL/kg) diluted in 20 mL of 5% dextrose and infused over one hour, with two additional doses administered at 24-hour intervals (n = 35), or an equal-volume placebo consisting of normal saline administered on the same schedule (n = 35). No therapeutic hypothermia was administered. Serum MgSO₄ concentrations were measured at 72 hours, and outcomes included neurological status at discharge (suck reflex and feeding), cranial CT findings at day 14, and safety parameters. MgSO₄-treated infants demonstrated a significantly higher rate of normal neurological outcome at discharge, including improved sucking and feeding (71.4% vs 40%, p = 0.008), and fewer abnormal CT findings at day 14 compared with controls (11.4% vs 37.1%, p = 0.012). Overall, early postnatal MgSO₄ administration was effective in improving short-term neurological outcomes. No clinical neurodevelopmental follow-up was performed in this study. Rahman et al. (2015) 19 conducted a multicenter in Qatar, Turkey, Saudi Arabia, Egypt, Malaysia, and Abu Dhabi, double-blind randomized controlled pilot trial including 60 term and near-term neonates (≥ 35 weeks’ gestation) with moderate-to-severe HIE (defined by 10-min Apgar < 5, ventilation at 10 min, pH < 7.00, OR base deficit ≥ 16 within 60 min), all treated with standard therapeutic hypothermia initiated within 6 hours of birth. Infants were randomized to receive therapeutic hypothermia plus intravenous MgSO₄ at a dose of 250 mg/kg per dose (10% solution, 2.5 mL/kg), administered as a slow infusion over 30 minutes once daily for three days (n = 29), or therapeutic hypothermia plus an equal-volume normal saline placebo (n = 31). Primary outcomes focused on short-term safety and pre-discharge adverse events, including mortality, seizures, hypotension, coagulopathy, renal failure, intracranial hemorrhage, and other major neonatal morbidities. Baseline characteristics and HIE severity were comparable between groups. No significant differences were observed in mortality or any short-term adverse outcomes, and MgSO₄ did not increase the risk of hypotension or other complications when combined with hypothermia. Overall, adjunctive MgSO₄ therapy during therapeutic hypothermia is safe and well tolerated, while emphasizing that larger trials are required to determine long-term neurodevelopmental efficacy. No clinical neurodevelopmental follow-up was performed in this study. Rashid et al. (2015) 20 conducted in Pakistan a single-center open-label randomized controlled trial including 200 term neonates (> 36 weeks’ gestation) with moderate-to-severe HIE (stages II-III, no definition provided) admitted within 6 hours of birth. Infants were randomized equally to receive either intravenous MgSO₄ at a dose of 250 mg/kg per dose, diluted in 20 mL normal saline and infused over 1 hour at 0, 24, and 48 hours of life (n = 100), or an equal-volume normal saline placebo administered on the same schedule (n = 100), in addition to standard supportive NICU care. No therapeutic hypothermia was administered. Primary outcomes focused on short-term neurological recovery, particularly establishment of oral feeding and status at discharge or by day 14 of life, with secondary assessment of mortality. MgSO₄-treated infants demonstrated significantly higher rates of oral feeding at discharge (72% vs 31%, p = 0.001), earlier discharge, and lower in-hospital mortality (13% vs 23%) compared with controls. Overall, postnatal MgSO₄ significantly improves short-term neurological outcomes and may reduce early mortality in term neonates with moderate-to-severe perinatal asphyxia, while acknowledging the need for multicenter trials to validate effects on mortality and long-term neurodevelopment. No clinical neurodevelopmental follow-up was performed in this study. Ahmed et al. (2016) 21 conducted in India a prospective open-label randomized controlled study including 80 term, appropriate-for-gestational-age neonates with severe birth asphyxia (defined as 1-min Apgar score ≤ 3 and 5-min Apgar score ≤ 6), who were randomly allocated to MgSO₄ (n = 40) or to standard care alone (n = 40). The intervention consisted of intravenous MgSO₄ administered within 30 minutes of birth as a loading dose of 250 mg/kg, followed by two additional doses of 125 mg/kg at 24 and 48 hours of life, infused in 5% dextrose over 30 minutes. No therapeutic hypothermia was administered. Serial serum MgSO₄ concentrations were measured at 0, 12, 24, 48, and 72 hours, alongside continuous monitoring of heart rate, respiratory rate, oxygen saturation, blood pressure, and mean arterial pressure. MgSO₄-treated infants achieved significantly higher serum MgSO₄ concentrations within the proposed neuroprotective range (1.5–2.2 mmol/L) compared with controls, without significant alterations in cardiorespiratory or hemodynamic parameters. Although the incidence of hypoxic–ischemic encephalopathy, neonatal seizures, and apnoeic spells was lower in the MgSO₄ group, these differences did not reach statistical significance, and mortality was identical in both groups. Overall, the MgSO₄ regimen was found to be safe, achieved serum concentration within the neuroprotective range, and was associated with better immediate neurological outcomes. No clinical neurodevelopmental follow-up was performed in this study. Savitha et al. (2016) 22 conducted in India a randomized controlled single-blinded trial including 120 term neonates with perinatal asphyxia. The criteria for inclusion were very expansive (Apgar score < 7 at 1- min). Infants were randomized to receive either intravenous MgSO₄ at a dose of 250 mg/kg per dose (1 mL/kg of 10% MgSO₄ diluted in 20 mL of 5% dextrose), infused over 1 hour within 6 hours of birth and repeated at 24 and 48 hours (n = 60), or standard NICU care without MgSO₄ supplementation (n = 60). No therapeutic hypothermia was administered. Baseline characteristics and HIE severity were comparable between groups, and serum MgSO₄ concentration in the intervention group reached the proposed neuroprotective range without hemodynamic or respiratory adverse effects. MgSO₄-treated infants demonstrated significantly earlier seizure control, shorter duration of neurological abnormalities, earlier initiation of enteral feeding, and a higher proportion of normal neurological examination and neuromotor tone at discharge compared with controls, while mortality did not differ significantly. Overall, early postnatal intravenous MgSO₄ improves short-term neurological recovery and feeding outcomes in term neonates with perinatal asphyxia. No clinical neurodevelopmental follow-up was performed in this study. Sreenivasa et al. (2017) 23 conducted in India a prospective randomized controlled open-label study including 100 term neonates with perinatal asphyxia, equally allocated to a MgSO₄ treatment group (n = 50) or a control group receiving standard NICU care alone (n = 50). Eligible infants were ≥ 36 weeks’ gestation with severe perinatal depression (defined as 1-min Apgar < 3 and 5-min Apgar < 6), excluding congenital anomalies or maternal exposure to MgSO₄ or sedative drugs. The intervention consisted of intravenous MgSO₄ at a dose of 250 mg/kg per dose (1 mL/kg of 10% MgSO₄ diluted in 20 mL of 5% dextrose), infused over 1 hour within 6 hours of birth and repeated at 24 and 48 hours. No therapeutic hypothermia was administered. Outcomes included seizure control, time to initiation of feeding, neurological recovery, serum MgSO₄ concentrations, and short-term adverse events. MgSO₄-treated infants demonstrated significantly better seizure control with fewer ongoing seizures at 24 hours, earlier establishment of enteral feeding, shorter duration of neurological abnormalities, and fewer abnormal neurological findings at discharge, while mortality and major adverse effects did not differ between groups. Overall, early postnatal intravenous MgSO₄ is safe and improves short-term neurological outcomes in term neonates with perinatal asphyxia. No clinical neurodevelopmental follow-up was performed in this study. Gulczynska et al. (2018) 24 conducted in Poland a multicenter randomized controlled open-label trial in 75 neonates born at ≥ 36 weeks’ gestation with perinatal asphyxia and moderate-to-severe HIE (defined as 10-min Apgar ≤ 5, or pH < 7.1/base deficit ≥ 16, or mechanical ventilation for ≥ 10 min), all treated with standard therapeutic hypothermia initiated within 6 hours of birth. Infants were randomized to receive therapeutic hypothermia alone (n = 37) or therapeutic hypothermia plus MgSO₄ (n = 38). The intervention consisted of three intravenous doses of MgSO₄ at 250 mg/kg, administered as 1-hour infusions at 24-hour intervals over three consecutive days, using a 20% MgSO₄ solution, with serial monitoring of serum MgSO₄ concentrations and cardiorespiratory parameters. Primary outcome was in-hospital mortality, and secondary outcomes included short-term neurological status (Thompson score), time to full oral feeding, duration of hospitalization, and safety outcomes. Magnesium sulfate supplementation did not reduce mortality but was associated with significantly improved neurological scores at day 5, earlier establishment of oral feeding, and shorter hospitalization, without increased risk of hypotension, coagulopathy, intracranial hemorrhage, or other major adverse effects. Overall, MgSO₄ could safely be combined with therapeutic hypothermia and may accelerate short-term neurological recovery. No clinical neurodevelopmental follow-up was performed in this study. El-Farargy et al (2019) 25 from Egypt studied the effect of added MgSO₄ therapy in infants with moderate HIE [defined as Apgar score < 5 at 5 min, umbilical artery acidemia (pH < 7.0 and/or base deficit ≥ 12 mmol/L), and evidence of moderate HIE using modified Sarnat score 26 . Sixty neonates were randomized to MgSO₄ (250 mg/kg IV once daily for 3 days) plus Melatonin or Melatonin alone. The design was apparently not blinded. Serum S100-B, a marker of Central Nervous System (CNS) damage, concentrations did not differ between groups at enrollment. This study found a significant decline in S100-B at days 2 and 6 in the MgSO₄-Melatonin group compared with controls, (median = 8 vs 12 on day 2, p = 0.001, and median = 3 vs 10.5 on day 6, p < 0.001), suggesting attenuation of neuronal injury. No clinical neurodevelopmental follow-up was performed in this study. Nonomura et al. (2019) 27 conducted in Japan a prospective, single-arm, open-label pilot study to assess the safety and feasibility of combination therapy with erythropoietin, MgSO₄, and therapeutic hypothermia in neonates with HIE (defined by 10-min Apgar ≤ 5, ventilation at 10 min, or pH < 7.00/base deficit ≥ 16 within 60 min). Nine neonates born at ≥ 36 weeks’ gestation who met institutional criteria for hypothermia therapy (including clinical and biochemical evidence of perinatal asphyxia, moderate-to-severe encephalopathy, and abnormal aEEG) were enrolled, and all interventions were initiated within 6 hours of birth (mean 3.9 h). All infants received whole-body hypothermia at 33.5°C for 72 h, intravenous erythropoietin 300 U/kg every other day for 2 weeks, and intravenous MgSO₄ 250 mg/kg infused over 2 hours once daily for 3 days, alongside continuous dopamine infusion. Safety outcomes included in-hospital death, serious cardiopulmonary events, and predefined adverse events; short-term outcomes included ventilation status, oral feeding at discharge, and brain Magnetic Resonance imaging (MRI) at 14 days, while neurodevelopment was assessed at 18 months using the Kyoto Scale of Psychological Development. No deaths or serious adverse events related to treatment were observed, and all infants completed therapy; eight established oral feeding by discharge, two had abnormal MRI findings, and at 18 months three of eight followed infants had severe neurodevelopmental disability. Overall, the combined use of erythropoietin, MgSO₄, and therapeutic hypothermia is feasible and appears safe, while emphasizing that the study was not designed to assess efficacy and that controlled trials are required to evaluate neuroprotective benefit. No clinical neurodevelopmental follow-up was performed in this study. Firoz et al. (2020) 28 conducted in Bangladesh a randomized placebo-controlled single-blinded trial in 50 term neonates admitted within 6 hours of birth with moderate or severe perinatal asphyxia, classified according to Sarnat staging [30]. Infants were randomized to receive intravenous MgSO₄ at a dose of 250 mg/kg per dose, diluted in 20 mL of 5% dextrose and infused over 1 hour, repeated every 24 hours for three doses (n = 25), or an equal-volume placebo consisting of normal saline infused in an identical manner (n = 25), in addition to standard supportive care. No therapeutic hypothermia was administered. Outcomes included short-term neurological recovery parameters, cranial ultrasonography, EEG findings, serum MgSO₄ concentrations, and safety measures. MgSO₄-treated infants with moderate HIE demonstrated significantly earlier seizure control, faster normalization of cry and activity, earlier establishment of full oral feeding, and shorter hospital stay compared with placebo, whereas no statistically significant benefit was observed in infants with severe HIE. Neuroimaging and EEG findings at day 14 did not differ between groups, and no significant hemodynamic adverse effects were reported. Overall, postnatal MgSO₄ is safe and may improve short-term neurological recovery in moderate, but not severe, hypoxic-ischemic encephalopathy, without demonstrated effects on imaging or mortality. No clinical neurodevelopmental follow-up was performed in this study. Abdel-Aziz et al. (2021) 29 conducted in Egypt a randomized controlled open-label trial including 36 term and near-term neonates with moderate-to-severe HIE (defined by 5-min Apgar ≤ 5, ventilation at 10 min, pH < 7.1/base deficit ≥ 16, or pre-delivery fetal distress signs), allocated equally into three groups: whole-body therapeutic hypothermia (TH) alone (n = 12), TH combined with MgSO₄ (n = 12), or supportive care only (n = 12). Cooling was initiated within 6 hours of birth and maintained for 72 hours. The adjunctive MgSO₄ regimen consisted of intravenous MgSO₄ at a dose of 250 mg/kg administered over 1 hour, once daily for three consecutive days, alongside dopamine infusion (5 µg/kg/min). Outcomes included short-term clinical measures (seizure frequency, duration of respiratory support, time to enteral feeding), neurological scores, and brain MRI findings. Infants treated with TH plus MgSO₄ demonstrated significantly fewer seizures, shorter respiratory support duration, earlier initiation of feeding, and more favorable short-term clinical outcomes compared with TH alone or supportive care, without safety concerns. Overall, MgSO₄ may provide additive short-term neuroprotective benefit when used as an adjunct to therapeutic hypothermia. No clinical neurodevelopmental follow-up was performed in this study. Iqbal et al. (2021) 30 conducted in Pakistan a prospective double-blind randomized controlled trial including 62 term or near-term neonates (> 35 weeks’ gestation) with moderate-to-severe HIE (defined by inability to initiate or sustain breathing at birth with clinical encephalopathy features or seizures), admitted within 24 hours of birth. Infants were randomized to receive intravenous MgSO₄ at a dose of 250 mg/kg per dose, diluted to a volume of 3 mL/kg and infused over one hour, repeated at 24 and 48 hours (n = 31), or an equal-volume placebo consisting of 10% dextrose infused in an identical schedule (n = 31), in addition to standard supportive care. No therapeutic hypothermia was administered. Short-term outcomes included seizure control, time to initiation of feeding, duration of hospitalization, cranial ultrasonography findings, and mortality at discharge, while long-term outcome was assessed at six months using the ShaMaq Developmental Inventory. MgSO₄-treated infants demonstrated significantly earlier seizure control, earlier initiation of feeding, and shorter hospital stay compared with controls, without significant differences in cranial ultrasound abnormalities or mortality. At six months, no statistically significant improvement in neurodevelopmental outcome was observed. Overall, postnatal MgSO₄ improved short-term neurological recovery but did not confer measurable long-term neurodevelopmental benefit at six months. No clinical neurodevelopmental follow-up beyond 6 months was performed in this study. Siddiqui et al (2021) 31 conducted in Pakistan a single-blinded RCT in which a repeated-dose regimen of MgSO₄ 250 mg/kg at 0, 24, and 48 hours was given to term neonates with HIE (defined by need for resuscitation at birth, with 1-min Apgar ≤ 3 and 5-min Apgar ≤ 7), diagnosed within 6 h of birth. Significant differences were reported in favor of MgSO₄ in terms of improved feeding, reduced seizure duration, and better neurological status at discharge. No long-term clinical neurodevelopmental assessment was reported. Khan et al. (2022) 32 conducted in Pakistan a prospective observational open-label study in a single tertiary neonatal unit in Pakistan, including 90 term neonates with moderate HIE (defined by 5-min Apgar score < 5, umbilical blood pH < 7.0, and clinical moderate HIE by Sarant staging). Neonates were randomly assigned to receive either combined therapy with MgSO₄ and melatonin (group 1; n = 45) or melatonin alone (group 2; n = 45). The intervention consisted of intravenous MgSO₄ at a dose of 250 mg/kg infused over 60 minutes on days 0, 1, and 3, in addition to enteral melatonin 10 mg/kg daily for five consecutive days; the comparator group received melatonin only. No therapeutic hypothermia was administered. Outcomes included serial arterial blood gas pH measurements, serum MgSO₄ concentrations, mortality, seizures, hypotension, renal failure, thrombocytopenia, and intracranial hemorrhage. The combination therapy group demonstrated significantly greater improvement in blood pH and higher serum MgSO₄ concentrations at days 3 and 7, as well as lower mortality compared with melatonin alone, while adverse event rates did not differ significantly between groups. Overall, MgSO₄ as adjunctive therapy to melatonin was associated with improved short-term clinical outcomes in neonates with HIE. No clinical neurodevelopmental follow-up was performed in this study. Nanda et al. (2022) 33 conducted in India a non-blinded randomized controlled trial including 227 neonates with moderate-to-severe perinatal asphyxia, admitted to a tertiary neonatal unit and randomized to receive intravenous MgSO₄ (n = 116) or standard care alone (n = 111). Eligible infants met clinical criteria for perinatal asphyxia (defined by 1-min Apgar < 3 or 5-min Apgar < 7, or moderate/severe encephalopathy within 24h with delayed cry) and were enrolled at admission; congenital anomalies and metabolic disorders were excluded. The intervention consisted of a loading dose of MgSO₄ 250 mg/kg infused over 1 hour in 20 mL of 5% dextrose at admission, followed by identical doses at 24 and 48 hours, in addition to standard supportive care. No therapeutic hypothermia was administered. Primary outcomes included seizure burden and anticonvulsant requirements, while secondary outcomes encompassed feeding patterns, duration of hospitalization, need for inotropic support, discharge status, and mortality; subgroup analyses were performed according to age at treatment initiation ( 24 h). MgSO₄-treated infants demonstrated significantly earlier initiation and achievement of full feeds, reduced seizure frequency and antiepileptic drug requirements, lower need for inotropes, shorter hospital stays, and higher discharge rates, with the greatest benefit observed when treatment was initiated within 6 hours of life. No significant adverse hemodynamic or biochemical effects were reported. Overall, early postnatal intravenous MgSO₄ is safe and associated with improved short-term clinical outcomes in neonates with moderate-to-severe perinatal asphyxia, with efficacy appearing time-dependent. No clinical neurodevelopmental follow-up was performed in this study. Kumar et al (2023) 34 conducted in India a randomized controlled trial to determine whether adjunctive MgSO₄ provides additional neuroprotective benefit when combined with therapeutic hypothermia in term neonates with HIE (defined by pH ≤ 7 / base deficit ≥ 12 within 1h, or 10-min Apgar ≤ 5 / ventilation ≥ 10 min with acute perinatal event). Overall, 134 infants were randomized to receive intravenous MgSO₄ (250 mg/kg once daily for three days, initiated within six hours of birth) plus therapeutic hypothermia, or hypothermia alone. The primary endpoint was a composite of mortality and/or major neurodevelopmental disability at one year of age, assessed using the Developmental Assessment Scale for Indian Infants. Secondary outcomes included neurological status at discharge, and total serum antioxidant status, malondialdehyde, a marker of CNS damage, as well as acute adverse events (hypotension, respiratory depression). Among 115 infants included in the primary analysis, the composite outcome did not differ significantly between the MgSO₄ group (24%) and the control group (33%) (RR 0.72; 95% CI 0.40–1.30; p = 0.30). Secondary outcomes and adverse events were also comparable between groups. Kumar et al concluded that MgSO₄ does not provide additive neuroprotection in cooled term infants with HIE. No clinical neurodevelopmental follow-up was performed in this study. Narrative reviews (N = 2) that appeared in our systematic search included the work of Muralidharan et al (2025) 35 that included all the studies already mentioned above. Additional narrative review of Whitelaw et al (2002) 36 summarized non-clinical study in piglets (Penrice, 1997) 37 and a phase I/ Pharmacokinetic study (Levene et al. (1995) 38 . That work conducted a phase I physiological and pharmacokinetic non-randomized and non-blinded study in 15 term neonates with birth asphyxia (Apgar score < 6 at 10 minutes), evaluated within 12 hours of delivery, to assess the acute effects of two different doses of intravenous MgSO₄. Seven infants received 400 mg/kg MgSO₄ and eight received 250 mg/kg MgSO₄, administered as a single intravenous infusion over 10–30 minutes. Outcomes included serial measurements of serum MgSO₄ concentrations, mean arterial pressure, heart rate, respiratory function, muscle tone, and EEG activity. The higher dose (400 mg/kg) resulted in significant hypotension and prolonged respiratory depression, whereas the lower dose (250 mg/kg) achieved serum MgSO₄ concentrations within the putative neuroprotective range without hypotension, although transient respiratory depression occurred in one infant. EEG activity was not altered at either dose. Overall, 400 mg/kg MgSO₄ carries an unacceptable risk of hypotension, while 250 mg/kg appears physiologically safer, and proposed a multi-dose regimen (250 mg/kg followed by 125 mg/kg at 24 and 48 hours) for future neuroprotection trials. Meta-analyses We attempted to group the various studies having similar entry criteria and design (in terms of magnesium administration protocol) and which reported similar outcomes. Three studies reported biochemical indices of brain injury: Khashaba et al. (2006) 14 , El-Farargy et al. (2019) 25 and Nonomura et al. (2019) 27 . Overall, marked heterogeneity exists in marker type, biological matrix, sampling schedule, and clinical context, precluding statistical aggregation or meta-analysis. Thus, in terms of brain injury biochemical indices, no meta-analyses could be conducted, and we are left with the individual qualitative analysis of each one of them (as reported above). Nine studies had similar entry criteria and magnesium administration protocols. However, they did not report universally the same outcomes. Table 1 depicts the various outcomes analyzed in the above-mentioned clinical trials. Meta-analyses were conducted on each outcome, based on the studies that reported these specific outcomes. Table 1 Summary of outcomes reported across studies included in the meta-analysis. Outcome Groenendaal 2002 Khashaba 2006 Bhat 2009 Hossain 2013 Rahman 2015 Savitha 2016 Firoz 2020 Siddiqui 2021 Iqbal 2021 Meta-analysis eligibility In-hospital / pre-discharge mortality Yes No Yes Yes Yes Yes Yes Yes Yes Eligible (primary) Seizure control Yes No No* Yes Yes Yes Yes Yes Yes Eligible (secondary) Neurological status at discharge No† No Yes Yes No Yes Yes Yes No Eligible (secondary) Time to establish oral/enteral feeding No No Yes Yes No Yes No Yes Yes Eligible (secondary) EEG / aEEG abnormalities aEEG No No EEG No No EEG No No Not eligible (heterogeneous modality) Neuroimaging abnormalities (CT/US) No No CT No No No US No US Not eligible (timing/definition heterogeneous) Biochemical markers No Yes No No No No No No No Not eligible (non-clinical endpoints) Long-term neurodevelopment Yes (24 mo. Study interrupted) No No No No No No No Yes (6 mo) Not eligible (insufficient overlap) DISCUSSION We identified and analyzed 24 clinical trials evaluating postnatal MgSO₄ administration within the first 12 hours of life in neonates with encephalopathy. A previous systematic review published in this journal identified only five such trials, highlighting the substantial expansion of the evidence base. Most studies reported that after 3 doses of 250 mg MgSO₄, magnesium concentrations in blood reached levels considered to be neuroprotective in preterm infants (1.2–3.77 mmol/L) 5,7,13,25,36 . All the studies included were conducted in term populations. MgSO₄ administration was generally reported as safe across studies, with no clinically significant adverse effects on hemodynamic stability, respiratory function, or mortality. Most studies reported improved short-term outcomes in the MgSO₄ group, particularly with respect to seizure control, feeding, and neurological status at discharge. No study demonstrated worse outcomes with MgSO₄. When feasible, meta-analyses confirmed significant benefits in seizure occurrence, feeding establishment, and neurological status at discharge. However, no statistically significant effect on mortality was observed. Several limitations warrant consideration. First, substantial heterogeneity exists across studies in patient populations (including inconsistent and outdated definitions of neonatal asphyxia), study design (randomization and blinding), and outcome selection. Outcomes varied widely, encompassing both safety (e.g., mortality, hemodynamics, oxygenation) and efficacy endpoints (e.g., seizures, neurological status at discharge, feeding outcomes, and heterogeneous biochemical and imaging markers of brain injury). Second, most trials of postnatal MgSO₄ were conducted prior to the adoption of therapeutic hypothermia and predominantly in low- and middle-income settings. Only one study evaluated MgSO₄ as an adjunct to hypothermia, focusing primarily on safety rather than efficacy. Accordingly, the effect of MgSO₄ in the era of hypothermia remains largely unknown, and no large randomized controlled trials from high-resource settings have addressed this question. Existing evidence is therefore mainly applicable to contexts in which hypothermia is unavailable. Nevertheless, given its low cost and accessibility, MgSO₄ may represent a pragmatic alternative where hypothermia cannot be implemented. Third, long-term neurodevelopmental data are scarce. Only one study reported structured outcomes at 6 months, with no significant between-group differences. No conclusions can therefore be drawn regarding sustained neurodevelopmental benefit. Fourth, evidence on MgSO₄-associated neuroprotection based on biochemical markers remains fragmented. Future studies require standardized biomarker selection, consistent timing of measurements, and integration with neuroimaging to enable mechanistic interpretation and comparability across studies. Fifth, despite strong evidence supporting antenatal MgSO₄ for neuroprotection in preterm infants, no randomized double-blind trials have evaluated early postnatal administration in this population. This gap is particularly relevant for preterm neonates following precipitous deliveries without antenatal exposure and represents a priority for future research. CONCLUSION Postnatal MgSO₄ appears safe and is consistently associated with improved short-term clinical outcomes in neonates with HIE, particularly in seizure control, neurological status at discharge, and feeding establishment. However, no significant reduction in mortality has been demonstrated, and evidence regarding long-term neurodevelopmental benefit remains extremely limited. Most available data derive from pre-hypothermia-era studies or settings where therapeutic hypothermia is not routinely available. Consequently, the role of MgSO₄ as an adjunct to hypothermia remains uncertain. Its definitive clinical value requires confirmation through adequately powered trials with standardized protocols and long-term follow-up. Policy Implications Based on the Main Findings Based on the synthesis of the available evidence, policy considerations should be structured according to three distinct neonatal populations, reflecting differences in resource availability, current standards of care, and biological vulnerability. 1. Term infants born in high-income countries where therapeutic hypothermia is available In term infants with moderate-to-severe neonatal encephalopathy treated in developed healthcare systems where therapeutic hypothermia is standard of care, postnatal MgSO₄ appears safe and is consistently associated with improved short-term outcomes, particularly in seizure control, neurological examination at discharge, and establishment of oral feeding. However, there is no convincing evidence of reduced mortality, and there is essentially no robust evidence regarding long-term neurodevelopmental outcomes, especially when MgSO₄ is administered in conjunction with hypothermia. From a policy perspective, MgSO₄ should not be adopted as routine adjunctive therapy alongside hypothermia outside the framework of adequately powered randomized controlled trials with predefined long-term neurodevelopmental endpoints. In these settings, its role remains investigational, and future research must specifically assess whether magnesium provides incremental benefit beyond established cooling protocols. 2. Term infants born in low- and middle-income countries where therapeutic hypothermia is not available In settings where therapeutic hypothermia is unavailable or inconsistently implemented, there is no evidence regarding both short and long term outcomes of infants born with perinatal asphyxia, and standards of neuroprotective care are often variable. Importantly, only one study addressed the safety of MgSO₄ administration in conjunction with hypothermia, and it focused primarily on safety rather than efficacy outcomes. Therefore, in countries where cooling is not part of routine care, policymakers should carefully consider whether MgSO₄ loading or structured administration could be incorporated into standardized protocols. Any such implementation should ideally occur within prospective registries or pragmatic trials designed to generate high-quality data on both safety and clinically meaningful outcomes. 3. Preterm infants Therapeutic hypothermia is currently contraindicated in preterm infants because of safety concerns and lack of supporting evidence. At the same time, no randomized controlled trials have evaluated early postnatal MgSO₄ specifically in preterm neonates with hypoxic-ischemic injury. This represents a critical knowledge gap. The question is particularly relevant in cases of abrupt placental abruption or precipitous delivery, where antenatal MgSO₄ could not be administered and hypothermia is not an option. In this population, evaluation of MgSO₄ as a potential neuroprotective intervention warrants careful investigation through dose-finding and safety trials before any policy recommendations can be made. Until such data are available, routine postnatal magnesium use in preterm infants cannot be recommended. Overall Policy Direction Across all populations, the consistent safety profile of postnatal MgSO₄ supports continued scientific evaluation. However, the absence of robust long-term neurodevelopmental data precludes definitive policy endorsement. Future studies must be multicenter, adequately powered, and include standardized dosing regimens, harmonized short-term outcomes, and mandatory long-term follow-up beyond infancy. Only through such rigorous investigation can the true role of postnatal MgSO₄ in neonatal encephalopathy be clarified and translated into evidence-based policy. Abbreviations NE neonatal encephalopathy HIE hypoxic-ischemic encephalopathy MgSO₄ magnesium sulfate aEEG amplitude-integrated electroencephalography RCTs randomized controlled trials CSF cerebrospinal fluid MRI magnetic resonance imaging CI confidence interval RR relative risk Declarations Conflicts of Interest: The authors declare no conflicts of interest. Availability of Data and Materials: The data supporting the findings of this study are available within the article. Acknowledgement: None to declare. Author Contributions: Conceptualization, F.B.M. and Y.D.; methodology, F.B.M. and Y.D.; formal analysis, Y.D.; investigation, Y.D. and F.B.M.; data curation, Y.D.; writing- original draft preparation, Y.D.; writing- review and editing, F.B.M., I.A., and J.M.; supervision, F.B.M. All authors have read and agreed to the published version of the manuscript. Funding : This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. References Shankaran S. Therapeutic hypothermia for neonatal encephalopathy. Curr Opin Pediatr 2015;27:152–157. Jacobs SE, Berg M, Hunt R, et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013;1:CD003311. Chollat C, Sentilhes L, Marret S. Fetal neuroprotection by magnesium sulfate. Front Neurol 2018;9:247. Shepherd ES, Goldsmith S, Doyle LW, et al. Magnesium sulphate for women at risk of preterm birth. Cochrane Database Syst Rev 2024;5:CD004661. Groenendaal F, Rademaker CM, Toet MC, de Vries LS. Effects of magnesium sulphate on EEG. Acta Paediatr 2002;91:1073–1077. Ichiba H, Tamai H, Negishi H, et al. Magnesium sulfate infusion for birth asphyxia. Pediatr Int 2002;44:505–509. Bhat MA, Charoo BA, Bhat JI, et al. Magnesium sulfate in perinatal asphyxia. Pediatrics 2009;123:e764-e769. Page MJ, McKenzie JE, Bossuyt PM, et al. PRISMA 2020 statement. BMJ 2021;372:n71. Tagin M, Shah PS, Lee KS. Magnesium for neonatal encephalopathy. J Perinatol 2013;33:663–669. Gowda BB, Rath C, Muthusamy S, et al. Magnesium sulfate outcomes meta-analysis. J Pediatr 2023;262:113610. Fei Q, Wang D, Yuan T. Adjuvant therapies for hypothermia. Indian J Pediatr 2024;91:235–241. Yang M, Wang K, Liu B, et al. Hypoxic-ischemic encephalopathy therapies. Mol Neurobiol 2025;62:2105–2122. Gathwala G, Khera A, Singh I. Magnesium therapy in asphyxia. Indian J Pediatr 2006;73:209–212. Khashaba MT, Shouman BO, Shaltout AA, et al. Magnesium in neonatal asphyxia. Brain Dev 2006;28:375–379. Gathwala G, Khera A, Singh J, et al. Magnesium neuroprotection. J Pediatr Neurosci 2010;5:102–104. Hossain M, Mannan M, Yeasmin F, et al. Magnesium sulfate outcome. Mymensingh Med J 2013;22:727–735. Dixon BJ, Reis C, Ho WM, et al. Neuroprotection after HIE. Int J Mol Sci 2015;16:22368–22401. Mahmood T, Zulfiqar R, Farah T, et al. Magnesium sulfate outcomes. J Rawalpindi Med Coll 2015;19. Rahman SU, Canpolat FE, Oncel MY, et al. Mag Cool study. J Clin Neonatol 2015;4:158–163. Rashid A, Fatima N, Asim M, et al. Magnesium sulphate outcome. Pak Postgrad Med J 2015;26:2–5. Ahmed FKR, Sultana NS. Safety of magnesium sulphate. Int J Contemp Pediatr 2016;3:80–85. Savitha M, Rajprakash R. Magnesium sulphate effect. Int J Contemp Pediatr 2016;3:150–154. Sreenivasa B, Lokeshwari K, Joseph N. Magnesium sulphate complications. Sri Lanka J Child Health 2017;46:148. Gulczynska E, Gadzinowski J, Nowiczewski M, et al. Hypothermia plus magnesium feasibility. Neonat Pediatr Med 2018;4:165. El-Farargy M, Soliman N. Magnesium sulfate and melatonin trial. J Neonatal Perinatal Med 2019;12:379–384. Sarnat HB, Sarnat M. Neonatal encephalopathy. Arch Neurol 1976;33:696–705. Nonomura M, Harada S, Asada Y, et al. Combination therapy HIE. BMC Pediatr 2019;19:13. Firoz MMR. Magnesium sulphate effectiveness. ARC J Pediatr 2020;7:6–10. Abdel-Aziz SM, Abdel Rahman MSM, Shoreit AH, et al. Cooling and magnesium outcome. J Child Sci 2021;11:e280-e286. Iqbal N, Younus J, Malik M, et al. Magnesium sulfate efficacy. Cureus 2021;13:e16826. Siddiqui MA, Butt TK. Magnesium sulphate role. J Coll Physicians Surg Pak 2021;31:817–820. Khan MH, Ann Q, Khan MS, et al. Magnesium with melatonin. Cureus 2022;14:e21163. Nanda AK, Jalan A, Pradhan SK, et al. Magnesium infusion outcomes. Int J Health Sci 2022;6:13064–13075. Kumar C, Adhisivam B, Bobby Z, et al. Magnesium adjunct therapy. Indian J Pediatr 2023;90:886–892. Muralidharan O, Rehman S, Sihota D, et al. Post-asphyxial care. Neonatology 2025;122:84–105. Whitelaw A, Thoresen M. Clinical trials after asphyxia. Curr Opin Pediatr 2002;14:664–668. Penrice J, Amess PN, Punwani S, et al. Magnesium and cerebral energy failure. Pediatr Res 1997;41:443–447. Levene MI, Blennow M, Whitelaw A, et al. Magnesium dosing effects. Arch Dis Child Fetal Neonatal Ed 1995;73:F174-F177. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9362928","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":625750151,"identity":"6306cc59-433b-48a2-b8ae-ace5753f93b4","order_by":0,"name":"Joseph Mendlovic","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyElEQVRIiWNgGAWjYFACxgcHgKQciHngAXFamA1AWozBWhKI1QIiExtAJFFa5NubGQ/dqLiTPj/s8EOgLXZyug0EtBicOcxwOOfMs9yNt9MMgFqSjc0OENIikX/gcG7b4dyNsxNAWg4kbiOkRX7+Y4bDuf8OpxvOTv9AnBaGG8xALQ2HE+Slc4i0xeBMMtAvxw4bbpDOKTiQYECEX+TbDzN/zqk5LC8/O33zhw8VdnIEtSCsA6s0IFY52LoGUlSPglEwCkbBiAIA0oBLZVAJCLoAAAAASUVORK5CYII=","orcid":"","institution":"Shaare –Zedek Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Joseph","middleName":"","lastName":"Mendlovic","suffix":""},{"id":625750152,"identity":"e10d4aa2-6af1-4d31-a910-f3c0eb0545d5","order_by":1,"name":"Francis Mimouni","email":"","orcid":"","institution":"[email protected]","correspondingAuthor":false,"prefix":"","firstName":"Francis","middleName":"","lastName":"Mimouni","suffix":""},{"id":625750153,"identity":"3d72365a-362a-4ece-8e93-13c647677fe1","order_by":2,"name":"Yuval Yuval","email":"","orcid":"https://orcid.org/0009-0005-0556-335X","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Yuval","middleName":"","lastName":"Yuval","suffix":""},{"id":625750154,"identity":"5cf12fb9-0d3a-49d1-9d7c-274c030e147a","order_by":3,"name":"Iris Arad","email":"","orcid":"","institution":"Hebrew University of Jerusalem, Jerusalem, Israel","correspondingAuthor":false,"prefix":"","firstName":"Iris","middleName":"","lastName":"Arad","suffix":""}],"badges":[],"createdAt":"2026-04-09 04:10:55","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9362928/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9362928/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107948658,"identity":"19db9689-afa7-4dab-bc75-c6f5349cfb01","added_by":"auto","created_at":"2026-04-28 00:22:56","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":61779,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9362928/v1/2acb2aaa30e008139ef035bb.jpg"},{"id":108007054,"identity":"88d00b93-1184-420a-9f9f-7424c09a30f3","added_by":"auto","created_at":"2026-04-28 12:58:19","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":173995,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9362928/v1/1a5d10b4e33a5a18591d9687.jpg"},{"id":108009542,"identity":"8f44347b-bf33-431d-8ea0-36e3a9d5d5d9","added_by":"auto","created_at":"2026-04-28 13:10:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":540822,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9362928/v1/e710f9f1-29dd-4599-81ea-c532caad75ff.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"\u003cp\u003eMagnesium Sulfate for Brain Protection in Neonatal Encephalopathy: A Systematic Review\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eNeonatal encephalopathy (NE), most commonly resulting from intrapartum hypoxia-ischemia, remains a major cause of neonatal mortality and long-term neurodevelopmental impairment worldwide. Despite advances in perinatal care, survivors of moderate-to-severe hypoxic-ischemic encephalopathy (HIE) remain at high risk for epilepsy, cerebral palsy, cognitive impairment, and behavioral disorders\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Therapeutic hypothermia is the standard neuroprotective intervention for eligible term and near-term infants and has been shown to reduce death and disability. However, a substantial proportion of treated infants continue to experience adverse outcomes, highlighting the need for additional neuroprotective strategies\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMagnesium sulfate (MgSO₄) is a biologically plausible candidate for neuroprotection in NE. Its mechanisms of action target key components of the hypoxic-ischemic injury cascade, including excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptor activation, intracellular calcium influx, oxidative stress, and inflammation\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. By acting as a physiological NMDA receptor antagonist, MgSO₄ modulates calcium entry and downstream cellular injury pathways. It may also stabilize cellular membranes and influence cerebral vascular tone, further supporting its potential neuroprotective role\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. These properties, combined with its wide availability and established clinical use, have driven interest in MgSO₄ as a postnatal intervention in neonates with NE.\u003c/p\u003e \u003cp\u003eClinical interest in MgSO₄ has also been informed by strong evidence supporting its antenatal use for fetal neuroprotection in threatened preterm birth\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Large randomized trials and meta-analyses have demonstrated a reduction in the risk of cerebral palsy among preterm infants exposed to antenatal MgSO₄, leading to widespread adoption in clinical practice. Although the mechanisms and clinical contexts differ between preterm brain injury and term HIE, these findings provide a rationale for evaluating MgSO₄ as a postnatal neuroprotective agent.\u003c/p\u003e \u003cp\u003eOver the past two decades, multiple clinical studies have evaluated postnatal MgSO₄ administration in term and near-term neonates with perinatal asphyxia or NE. These studies have used a range of clinical and surrogate outcomes, including seizure burden, neurological examination at discharge, neuroimaging findings, and feeding ability. Early trials suggested potential short-term benefits without significant safety concerns. However, most studies were small, with heterogeneous inclusion criteria, dosing regimens, and outcome definitions.\u003c/p\u003e \u003cp\u003eWith the widespread adoption of therapeutic hypothermia, the role of MgSO₄ requires re-evaluation in the context of modern neonatal care. Combination neuroprotection is conceptually attractive, as hypothermia targets multiple downstream injury pathways and may complement agents that primarily modulate excitotoxicity. At the same time, combination therapy introduces potential interactions and increases the evidentiary threshold for demonstrating additional benefit. Existing studies of MgSO₄ in the era of hypothermia are limited, and prior meta-analyses have not demonstrated clear improvements in clinically meaningful outcomes such as death or long-term disability\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis systematic review aims to provide a comprehensive and updated synthesis of the evidence on postnatal MgSO₄ administration in neonates at risk of hypoxic-ischemic brain injury. We focus on clinically relevant outcomes, including mortality, seizures, neurological status, and neurodevelopment when available, as well as safety and feasibility considerations in both pre-hypothermia and contemporary clinical settings.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThis systematic review adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines and follows a protocol similar to that used in our previous work\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Parallel searches were conducted in MEDLINE, Embase, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials. We used broad search terms combined with thesaurus explode functions to maximize sensitivity. To improve specificity, both built-in filters and additional keywords were applied.\u003c/p\u003e \u003cp\u003eTwo search strategies were used. In the first, the terms \u0026ldquo;magnesium AND (neonate OR newborn OR infant)\u0026rdquo; were applied with language restricted to English. In the second, the term \u0026ldquo;magnesium\u0026rdquo; was used with filters for English language and age (infant, newborn). Reference lists of all included studies were manually screened to identify additional eligible articles.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eAll studies including neonates with encephalopathy or asphyxia receiving postnatal MgSO₄ and comparing them with appropriate controls were retained for full-text review. Our primary objective was to evaluate all studies for new evidence on MgSO₄ administration after HIE for the purpose of brain protection.\u003c/p\u003e \u003cp\u003eWe included in the final analyses only trials that included an appropriate control group. Titles and abstracts of records identified by the search were reviewed by 2 authors (YD and FBM) and either \"included\" or \"excluded\" as full-text articles. An Excel data collection form was used to extract and record information on design, methods and participants from each study. Disagreements were resolved through consensus among reviewers.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eAnalyses were performed using Review Manager (RevMan), version 5.4 (Cochrane Collaboration, Copenhagen, Denmark), for primary meta-analyses and forest plot generation, with supplementary analyses and graphical assessments conducted using Stata, version 16 (StataCorp, College Station, TX, USA). Data management and preliminary checks were conducted using Microsoft Excel.\u003c/p\u003e \u003cp\u003eMeta-analyses were pre-specified for randomized controlled trials evaluating postnatal MgSO₄ administration in term neonates with HIE. All studies were first analyzed and described qualitatively. Quantitative synthesis was restricted to studies with comparable eligibility criteria, MgSO₄ dosing and administration protocols, and sufficiently similar outcome definitions. Because outcomes were inconsistently reported across trials, separate meta-analyses were conducted for each outcome using only studies reporting that specific outcome. The primary outcome was in-hospital or pre-discharge mortality. Secondary outcomes included the occurrence of any clinical seizures, abnormal neurological status at discharge, and failure to establish oral or enteral feeding by discharge. Electroencephalographic or amplitude-integrated EEG findings, neuroimaging abnormalities, biochemical markers of brain injury, and long-term neurodevelopmental outcomes were excluded from quantitative analysis because of heterogeneity in biomarker type, biological matrix, sampling schedule, and clinical context, precluding any meaningful quantitative synthesis. These studies were therefore only analyzed and summarized qualitatively.\u003c/p\u003e \u003cp\u003eAll outcomes were dichotomous and were analyzed as risk ratios (RRs) with corresponding 95% confidence intervals (CIs). Meta-analyses were performed using a random-effects model based on the DerSimonian-Laird method, to account for anticipated clinical and methodological heterogeneity between studies. Statistical heterogeneity was assessed using the I\u0026sup2; statistic and between-study variance (τ\u0026sup2;). Forest plots were generated on a logarithmic scale, with RR values below 1 indicating a direction of effect favoring MgSO₄. Statistical significance was defined as a two-sided p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSensitivity Analysis\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eFormal sensitivity analyses were not performed because of the limited number of studies available per outcome and incomplete reporting of key methodological variables. To reduce potential bias, pooling was restricted to trials with broadly comparable designs and MgSO₄ administration protocols, and outcomes were combined only when definitions and timing were sufficiently aligned. Consistency of effect estimates across studies was assessed qualitatively through visual inspection of forest plots.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eOur search retrieved 7 Randomized Controlled Trials (RCTs), 5 systematic reviews, and 1 narrative review. The 5 systematic reviews and meta-analyses of Tagin (2013)\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, Gowda (2023)\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, Fei (2024)\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, Shepherd (2024)\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e and Yang (2024)\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e allowed to retrieve 17 additional RCTs (Fig.\u0026nbsp;1). We identified and analyzed 24 RCTs. They are described in a qualitative approach, and meta-analyses, whenever possible, are then performed, when similar MgSO₄ administration protocols are used.\u003c/p\u003e \u003cp\u003e \u003cb\u003eGroenendaal et al. (2002)\u003c/b\u003e \u003csup\u003e \u003cb\u003e \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e \u003c/b\u003e \u003c/sup\u003e conducted in the Netherlands a double-blind, randomized, placebo-controlled pilot study in 22 term neonates with perinatal asphyxia (defined as: \u0026ge;3 of: fetal hypoxia signs, umbilical pH\u0026thinsp;\u0026lt;\u0026thinsp;7.10, resuscitation need, Apgar\u0026thinsp;\u0026le;\u0026thinsp;5 at 10 min, or intermittent positive pressure ventilation at 10 min), to assess the effect of postnatal MgSO₄ on cerebral electrophysiological recovery using amplitude-integrated electroencephalography (aEEG). Infants were enrolled within 2\u0026ndash;3 h of birth and randomized to MgSO₄ (n\u0026thinsp;=\u0026thinsp;8) or placebo (n\u0026thinsp;=\u0026thinsp;14). MgSO₄ was administered shortly after admission (\u0026asymp;\u0026thinsp;250 mg/kg), with additional doses at 24 and 48 h, achieving a mean serum MgSO₄ concentration of \u0026asymp;\u0026thinsp;2.5 mmol/L.\u003c/p\u003e \u003cp\u003eThe primary outcome was change in aEEG background pattern over the first 24 h; secondary outcomes included seizures and neurodevelopment up to 24 months. MgSO₄ did not improve aEEG background activity. Instead, transient suppression of aEEG between 3 and 12 h of life occurred more frequently in the MgSO₄ group than in controls (6/8 vs 3/14, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), with no differences thereafter. There were no significant differences in seizure burden, antiepileptic treatment, mortality, or long-term neurodevelopmental outcomes. Postnatal MgSO₄ provided no evidence of neuroprotective benefit and might be associated with transient cerebral electrical suppression, leading to early termination of the trial. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eIchiba et al (2002)\u003c/b\u003e \u003csup\u003e \u003cb\u003e \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e \u003c/b\u003e \u003c/sup\u003e conducted in Japan a multicenter randomized controlled trial to evaluate whether postnatal MgSO₄ infusion (250 mg/kg/day for three days) is safe and improves outcomes in term infants with severe birth asphyxia (defined as: 5-min Apgar\u0026thinsp;\u0026le;\u0026thinsp;7 and either failure to initiate spontaneous respiration at 10 min or clinical seizures within 24h). The trial was sufficiently powered to detect a 50% reduction in adverse outcomes. Baseline characteristics and HIE severity were comparable between groups. In terms of safety, cardiovascular parameters (blood pressure, heart rate, respiratory rate) remained similar between groups. In terms of efficacy, MgSO₄ therapy did not reduce seizure duration or the need for assisted ventilation. However, survival with normal cranial CT, normal EEG, and successful oral feeding by 14 days were significantly more frequent in the MgSO₄ group than in controls (12/17 vs. 5/16, p\u0026thinsp;=\u0026thinsp;0.04). Overall, postnatal MgSO₄ at this dosing regimen is safe and may improve short-term neurological and feeding outcomes. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eGathwala et al (2006)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e \u003c/sup\u003e conducted in India a randomized controlled study in 40 term neonates with severe birth asphyxia (defined as: 1-min Apgar\u0026thinsp;\u0026lt;\u0026thinsp;3 and 5-min Apgar\u0026thinsp;\u0026lt;\u0026thinsp;6) to evaluate the safety and serum MgSO₄ concentration achieved with postnatal MgSO₄ administration. Infants were randomized to receive MgSO₄ (n\u0026thinsp;=\u0026thinsp;20) or standard care alone (n\u0026thinsp;=\u0026thinsp;20). The intervention consisted of an intravenous loading dose of 250 mg/kg within 30 min of birth, followed by two doses of 125 mg/kg at 24 and 48 h. Primary outcomes included serial serum MgSO₄ concentrations and continuous monitoring of cardiorespiratory and hemodynamic parameters. MgSO₄-treated infants achieved significantly higher serum MgSO₄ concentration at all post-treatment time points compared with controls (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with concentrations ranging from 1.47 to 1.92 mmol/L, within the proposed neuroprotective range. No significant adverse effects were observed on heart rate, respiratory rate, oxygen saturation, or mean arterial pressure. Overall, this MgSO₄ regimen was safe, well tolerated, and capable of maintaining sustained serum MgSO₄ concentrations. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eKhashaba et al. (2006)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e \u003c/sup\u003e conducted in Egypt a double-blind randomized controlled trial in 47 term neonates with perinatal asphyxia (defined as: 5-min Apgar score\u0026thinsp;\u0026le;\u0026thinsp;3 and/or delayed first breath\u0026thinsp;\u0026gt;\u0026thinsp;10 minutes after birth) to investigate cerebrospinal fluid (CSF) excitatory amino acid dynamics and the effect of postnatal MgSO₄. Infants were randomized within the first 24 hours of life to receive an i.v. 10% solution of MgSO₄ at a dose of 250 mg/kg administered over 10 minutes (n\u0026thinsp;=\u0026thinsp;23) or an equal volume of isotonic saline (0.9%) as placebo (n\u0026thinsp;=\u0026thinsp;24). CSF glutamate and aspartate concentrations were measured at baseline and at 72 hours, with concurrent clinical and neurological monitoring. Higher baseline CSF excitatory amino acid levels correlated significantly with increasing HIE severity, and concentrations declined over time in both groups. This study demonstrated that aspartate concentrations did not change significantly over time in either the placebo group (\u0026minus;\u0026thinsp;0.45\u0026thinsp;\u0026plusmn;\u0026thinsp;1.96 \u0026micro;Mol/L, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.34) or the MgSO₄ group (\u0026minus;\u0026thinsp;0.70\u0026thinsp;\u0026plusmn;\u0026thinsp;3.19 \u0026micro;Mol/L, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.37). There were no between-group differences in aspartate levels at baseline (3.52\u0026thinsp;\u0026plusmn;\u0026thinsp;2.40 vs. 3.92\u0026thinsp;\u0026plusmn;\u0026thinsp;2.59 \u0026micro;Mol/L, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.49) or at 72 hours (2.79\u0026thinsp;\u0026plusmn;\u0026thinsp;1.24 vs. 3.05\u0026thinsp;\u0026plusmn;\u0026thinsp;2.48 \u0026micro;Mol/L, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.92). Overall, postnatal administration of MgSO₄ had no effect on CSF aspartate concentrations compared with placebo, did not modify excitotoxic biomarker profiles in neonatal HIE, and provided no biochemical evidence of neuroprotection when administered after birth. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eBhat et al (2009)\u003c/b\u003e \u003csup\u003e \u003cb\u003e \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e \u003c/b\u003e \u003c/sup\u003e conducted in India a randomized, placebo-controlled clinical trial of 40 term neonates with severe perinatal asphyxia and moderate to severe HIE (defined as 3 of 4: fetal distress, ventilation\u0026thinsp;\u0026ge;\u0026thinsp;2 min, 5-min Apgar\u0026thinsp;\u0026le;\u0026thinsp;6, or pH\u0026thinsp;\u0026le;\u0026thinsp;7/base deficit\u0026thinsp;\u0026ge;\u0026thinsp;15 within 1h), treated with 3 doses of MgSO₄ infusion at 250 mg/kg per dose, 24 hours apart, or normal saline (placebo group) within hours of birth. At discharge, 22% of infants in the treatment group had neurologic abnormalities, compared with 56% (P\u0026thinsp;\u0026lt;\u0026thinsp;0.04) of infants in the placebo group. Infants in the treatment group were more likely to be receiving oral feedings (sucking) at discharge than were those in the placebo group (77% vs 37%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.02). No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eGathwala et al (2010)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e \u003c/sup\u003e extended their investigation from safety to clinical efficacy in a subsequent randomized controlled trial, conducted in India, comparing postnatal intravenous MgSO₄ (250 mg/kg within 30 minutes of birth, followed by 125 mg/kg at 24 and 48 hours) versus standard care in 40 term neonates with severe birth asphyxia (defined as: 1-min Apgar score\u0026thinsp;\u0026le;\u0026thinsp;3 AND 5-min Apgar score\u0026thinsp;\u0026le;\u0026thinsp;6), 20 in each group. Of these, 4 died and 16 continued follow-up assessment until the age of 6 months. Cranial CT and EEG were assessed by blinded evaluators, and surviving infants underwent neurodevelopmental assessment at 6 months using the Denver II screening test. Magnesium Sulfate was well tolerated and was associated with fewer EEG and CT abnormalities and more favorable short-term neurodevelopmental outcomes compared with controls; however, these differences were not statistically significant, suggesting a possible neuroprotective effect. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e\u003cb\u003eHossain et al. (2013)\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e conducted in Bangladesh a randomized, single-blinded, placebo-controlled clinical trial in 50 term neonates aged\u0026thinsp;\u0026lt;\u0026thinsp;12 hours with moderate or severe HIE following perinatal asphyxia (defined as history of perinatal asphyxia and one of: 5-min Apgar\u0026thinsp;\u0026le;\u0026thinsp;6, moderate/severe HIE, or seizures within 12h). Infants were randomized to receive either three intravenous doses of MgSO₄ at 250 mg/kg per dose, infused over 1 hour at 24-hour intervals, or three equal-volume doses of normal saline, in addition to standardized supportive care. No therapeutic hypothermia was administered. Serum MgSO₄ concentrations were measured at admission and at 48 hours, and infants were monitored for cardiorespiratory stability, neurological status, feeding ability, EEG abnormalities, and mortality. MgSO₄-treated infants achieved significantly higher serum MgSO₄ concentrations within the proposed neuroprotective range without significant hemodynamic or respiratory adverse effects. Compared with controls, the MgSO₄ group had significantly fewer neurological abnormalities at discharge (26% vs. 61%), higher rates of successful oral feeding by sucking (78% vs. 44%), and a greater proportion of good short-term outcomes (composite of normal neurological examination and oral feeding (60% vs. 32%), while EEG abnormalities and mortality (26%) did not differ significantly between groups. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eDixon et al (2015)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e \u003c/sup\u003e presented a narrative, mechanism-informed review of MgSO₄ in neonatal HIE (based upon acute intrapartum events causing moderate/severe encephalopathy, metabolic acidosis, and absence of other palsy causes), integrating preclinical mechanistic data and translational animal studies with available clinical evidence. In the clinical domain, his conclusions rely primarily on the systematic review by Tagin et al., rather than on individual randomized controlled trials. Based on this synthesis, Dixon concluded that despite strong biological plausibility and signals of short-term improvement without excess adverse effects, there is insufficient evidence that postnatal MgSO₄ reduces mortality or moderate-to-severe neurodevelopmental disability, and that inconsistent results, methodological heterogeneity, and concerns regarding temperature control and mortality trends warrant further adequately powered, rigorously controlled trials before clinical efficacy can be established. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMahmood et al. (2015)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e \u003c/sup\u003e conducted in Pakistan a randomized blinded controlled trial including 70 term neonates admitted within 6 hours of birth with moderate-to-severe hypoxic-ischemic encephalopathy (defined by: history of fetal distress, immediate ventilation\u0026thinsp;\u0026ge;\u0026thinsp;2 min, 5-min Apgar\u0026thinsp;\u0026lt;\u0026thinsp;6, and pH\u0026thinsp;\u0026lt;\u0026thinsp;7 / base deficit\u0026thinsp;\u0026gt;\u0026thinsp;15). Infants were randomized to receive intravenous MgSO₄ at a dose of 250 mg/kg (1 mL/kg) diluted in 20 mL of 5% dextrose and infused over one hour, with two additional doses administered at 24-hour intervals (n\u0026thinsp;=\u0026thinsp;35), or an equal-volume placebo consisting of normal saline administered on the same schedule (n\u0026thinsp;=\u0026thinsp;35). No therapeutic hypothermia was administered. Serum MgSO₄ concentrations were measured at 72 hours, and outcomes included neurological status at discharge (suck reflex and feeding), cranial CT findings at day 14, and safety parameters. MgSO₄-treated infants demonstrated a significantly higher rate of normal neurological outcome at discharge, including improved sucking and feeding (71.4% vs 40%, p\u0026thinsp;=\u0026thinsp;0.008), and fewer abnormal CT findings at day 14 compared with controls (11.4% vs 37.1%, p\u0026thinsp;=\u0026thinsp;0.012). Overall, early postnatal MgSO₄ administration was effective in improving short-term neurological outcomes. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eRahman et al. (2015)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e \u003c/sup\u003e conducted a multicenter in Qatar, Turkey, Saudi Arabia, Egypt, Malaysia, and Abu Dhabi, double-blind randomized controlled pilot trial including 60 term and near-term neonates (\u0026ge;\u0026thinsp;35 weeks\u0026rsquo; gestation) with moderate-to-severe HIE (defined by 10-min Apgar\u0026thinsp;\u0026lt;\u0026thinsp;5, ventilation at 10 min, pH\u0026thinsp;\u0026lt;\u0026thinsp;7.00, OR base deficit\u0026thinsp;\u0026ge;\u0026thinsp;16 within 60 min), all treated with standard therapeutic hypothermia initiated within 6 hours of birth. Infants were randomized to receive therapeutic hypothermia plus intravenous MgSO₄ at a dose of 250 mg/kg per dose (10% solution, 2.5 mL/kg), administered as a slow infusion over 30 minutes once daily for three days (n\u0026thinsp;=\u0026thinsp;29), or therapeutic hypothermia plus an equal-volume normal saline placebo (n\u0026thinsp;=\u0026thinsp;31). Primary outcomes focused on short-term safety and pre-discharge adverse events, including mortality, seizures, hypotension, coagulopathy, renal failure, intracranial hemorrhage, and other major neonatal morbidities. Baseline characteristics and HIE severity were comparable between groups. No significant differences were observed in mortality or any short-term adverse outcomes, and MgSO₄ did not increase the risk of hypotension or other complications when combined with hypothermia. Overall, adjunctive MgSO₄ therapy during therapeutic hypothermia is safe and well tolerated, while emphasizing that larger trials are required to determine long-term neurodevelopmental efficacy. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eRashid et al. (2015)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e \u003c/sup\u003e conducted in Pakistan a single-center open-label randomized controlled trial including 200 term neonates (\u0026gt;\u0026thinsp;36 weeks\u0026rsquo; gestation) with moderate-to-severe HIE (stages II-III, no definition provided) admitted within 6 hours of birth. Infants were randomized equally to receive either intravenous MgSO₄ at a dose of 250 mg/kg per dose, diluted in 20 mL normal saline and infused over 1 hour at 0, 24, and 48 hours of life (n\u0026thinsp;=\u0026thinsp;100), or an equal-volume normal saline placebo administered on the same schedule (n\u0026thinsp;=\u0026thinsp;100), in addition to standard supportive NICU care. No therapeutic hypothermia was administered. Primary outcomes focused on short-term neurological recovery, particularly establishment of oral feeding and status at discharge or by day 14 of life, with secondary assessment of mortality. MgSO₄-treated infants demonstrated significantly higher rates of oral feeding at discharge (72% vs 31%, p\u0026thinsp;=\u0026thinsp;0.001), earlier discharge, and lower in-hospital mortality (13% vs 23%) compared with controls. Overall, postnatal MgSO₄ significantly improves short-term neurological outcomes and may reduce early mortality in term neonates with moderate-to-severe perinatal asphyxia, while acknowledging the need for multicenter trials to validate effects on mortality and long-term neurodevelopment. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAhmed et al. (2016)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e \u003c/sup\u003e conducted in India a prospective open-label randomized controlled study including 80 term, appropriate-for-gestational-age neonates with severe birth asphyxia (defined as 1-min Apgar score\u0026thinsp;\u0026le;\u0026thinsp;3 and 5-min Apgar score\u0026thinsp;\u0026le;\u0026thinsp;6), who were randomly allocated to MgSO₄ (n\u0026thinsp;=\u0026thinsp;40) or to standard care alone (n\u0026thinsp;=\u0026thinsp;40). The intervention consisted of intravenous MgSO₄ administered within 30 minutes of birth as a loading dose of 250 mg/kg, followed by two additional doses of 125 mg/kg at 24 and 48 hours of life, infused in 5% dextrose over 30 minutes. No therapeutic hypothermia was administered. Serial serum MgSO₄ concentrations were measured at 0, 12, 24, 48, and 72 hours, alongside continuous monitoring of heart rate, respiratory rate, oxygen saturation, blood pressure, and mean arterial pressure. MgSO₄-treated infants achieved significantly higher serum MgSO₄ concentrations within the proposed neuroprotective range (1.5\u0026ndash;2.2 mmol/L) compared with controls, without significant alterations in cardiorespiratory or hemodynamic parameters. Although the incidence of hypoxic\u0026ndash;ischemic encephalopathy, neonatal seizures, and apnoeic spells was lower in the MgSO₄ group, these differences did not reach statistical significance, and mortality was identical in both groups. Overall, the MgSO₄ regimen was found to be safe, achieved serum concentration within the neuroprotective range, and was associated with better immediate neurological outcomes. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSavitha et al. (2016)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e \u003c/sup\u003e conducted in India a randomized controlled single-blinded trial including 120 term neonates with perinatal asphyxia. The criteria for inclusion were very expansive (Apgar score\u0026thinsp;\u0026lt;\u0026thinsp;7 at 1- min). Infants were randomized to receive either intravenous MgSO₄ at a dose of 250 mg/kg per dose (1 mL/kg of 10% MgSO₄ diluted in 20 mL of 5% dextrose), infused over 1 hour within 6 hours of birth and repeated at 24 and 48 hours (n\u0026thinsp;=\u0026thinsp;60), or standard NICU care without MgSO₄ supplementation (n\u0026thinsp;=\u0026thinsp;60). No therapeutic hypothermia was administered. Baseline characteristics and HIE severity were comparable between groups, and serum MgSO₄ concentration in the intervention group reached the proposed neuroprotective range without hemodynamic or respiratory adverse effects. MgSO₄-treated infants demonstrated significantly earlier seizure control, shorter duration of neurological abnormalities, earlier initiation of enteral feeding, and a higher proportion of normal neurological examination and neuromotor tone at discharge compared with controls, while mortality did not differ significantly. Overall, early postnatal intravenous MgSO₄ improves short-term neurological recovery and feeding outcomes in term neonates with perinatal asphyxia. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSreenivasa et al. (2017)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e \u003c/sup\u003e conducted in India a prospective randomized controlled open-label study including 100 term neonates with perinatal asphyxia, equally allocated to a MgSO₄ treatment group (n\u0026thinsp;=\u0026thinsp;50) or a control group receiving standard NICU care alone (n\u0026thinsp;=\u0026thinsp;50). Eligible infants were \u0026ge;\u0026thinsp;36 weeks\u0026rsquo; gestation with severe perinatal depression (defined as 1-min Apgar\u0026thinsp;\u0026lt;\u0026thinsp;3 and 5-min Apgar\u0026thinsp;\u0026lt;\u0026thinsp;6), excluding congenital anomalies or maternal exposure to MgSO₄ or sedative drugs. The intervention consisted of intravenous MgSO₄ at a dose of 250 mg/kg per dose (1 mL/kg of 10% MgSO₄ diluted in 20 mL of 5% dextrose), infused over 1 hour within 6 hours of birth and repeated at 24 and 48 hours. No therapeutic hypothermia was administered. Outcomes included seizure control, time to initiation of feeding, neurological recovery, serum MgSO₄ concentrations, and short-term adverse events. MgSO₄-treated infants demonstrated significantly better seizure control with fewer ongoing seizures at 24 hours, earlier establishment of enteral feeding, shorter duration of neurological abnormalities, and fewer abnormal neurological findings at discharge, while mortality and major adverse effects did not differ between groups. Overall, early postnatal intravenous MgSO₄ is safe and improves short-term neurological outcomes in term neonates with perinatal asphyxia. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eGulczynska et al. (2018)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e \u003c/sup\u003e conducted in Poland a multicenter randomized controlled open-label trial in 75 neonates born at \u0026ge;\u0026thinsp;36 weeks\u0026rsquo; gestation with perinatal asphyxia and moderate-to-severe HIE (defined as 10-min Apgar\u0026thinsp;\u0026le;\u0026thinsp;5, or pH\u0026thinsp;\u0026lt;\u0026thinsp;7.1/base deficit\u0026thinsp;\u0026ge;\u0026thinsp;16, or mechanical ventilation for \u0026ge;\u0026thinsp;10 min), all treated with standard therapeutic hypothermia initiated within 6 hours of birth. Infants were randomized to receive therapeutic hypothermia alone (n\u0026thinsp;=\u0026thinsp;37) or therapeutic hypothermia plus MgSO₄ (n\u0026thinsp;=\u0026thinsp;38). The intervention consisted of three intravenous doses of MgSO₄ at 250 mg/kg, administered as 1-hour infusions at 24-hour intervals over three consecutive days, using a 20% MgSO₄ solution, with serial monitoring of serum MgSO₄ concentrations and cardiorespiratory parameters. Primary outcome was in-hospital mortality, and secondary outcomes included short-term neurological status (Thompson score), time to full oral feeding, duration of hospitalization, and safety outcomes. Magnesium sulfate supplementation did not reduce mortality but was associated with significantly improved neurological scores at day 5, earlier establishment of oral feeding, and shorter hospitalization, without increased risk of hypotension, coagulopathy, intracranial hemorrhage, or other major adverse effects. Overall, MgSO₄ could safely be combined with therapeutic hypothermia and may accelerate short-term neurological recovery. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eEl-Farargy et al (2019)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e \u003c/sup\u003e from Egypt studied the effect of added MgSO₄ therapy in infants with moderate HIE [defined as Apgar score\u0026thinsp;\u0026lt;\u0026thinsp;5 at 5 min, umbilical artery acidemia (pH\u0026thinsp;\u0026lt;\u0026thinsp;7.0 and/or base deficit\u0026thinsp;\u0026ge;\u0026thinsp;12 mmol/L), and evidence of moderate HIE using modified Sarnat score\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Sixty neonates were randomized to MgSO₄ (250 mg/kg IV once daily for 3 days) plus Melatonin or Melatonin alone. The design was apparently not blinded. Serum S100-B, a marker of Central Nervous System (CNS) damage, concentrations did not differ between groups at enrollment. This study found a significant decline in S100-B at days 2 and 6 in the MgSO₄-Melatonin group compared with controls, (median\u0026thinsp;=\u0026thinsp;8 vs 12 on day 2, p\u0026thinsp;=\u0026thinsp;0.001, and median\u0026thinsp;=\u0026thinsp;3 vs 10.5 on day 6, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), suggesting attenuation of neuronal injury. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eNonomura et al. (2019)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e \u003c/sup\u003e conducted in Japan a prospective, single-arm, open-label pilot study to assess the safety and feasibility of combination therapy with erythropoietin, MgSO₄, and therapeutic hypothermia in neonates with HIE (defined by 10-min Apgar\u0026thinsp;\u0026le;\u0026thinsp;5, ventilation at 10 min, or pH\u0026thinsp;\u0026lt;\u0026thinsp;7.00/base deficit\u0026thinsp;\u0026ge;\u0026thinsp;16 within 60 min). Nine neonates born at \u0026ge;\u0026thinsp;36 weeks\u0026rsquo; gestation who met institutional criteria for hypothermia therapy (including clinical and biochemical evidence of perinatal asphyxia, moderate-to-severe encephalopathy, and abnormal aEEG) were enrolled, and all interventions were initiated within 6 hours of birth (mean 3.9 h). All infants received whole-body hypothermia at 33.5\u0026deg;C for 72 h, intravenous erythropoietin 300 U/kg every other day for 2 weeks, and intravenous MgSO₄ 250 mg/kg infused over 2 hours once daily for 3 days, alongside continuous dopamine infusion. Safety outcomes included in-hospital death, serious cardiopulmonary events, and predefined adverse events; short-term outcomes included ventilation status, oral feeding at discharge, and brain Magnetic Resonance imaging (MRI) at 14 days, while neurodevelopment was assessed at 18 months using the Kyoto Scale of Psychological Development. No deaths or serious adverse events related to treatment were observed, and all infants completed therapy; eight established oral feeding by discharge, two had abnormal MRI findings, and at 18 months three of eight followed infants had severe neurodevelopmental disability. Overall, the combined use of erythropoietin, MgSO₄, and therapeutic hypothermia is feasible and appears safe, while emphasizing that the study was not designed to assess efficacy and that controlled trials are required to evaluate neuroprotective benefit. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFiroz et al. (2020)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e \u003c/sup\u003e conducted in Bangladesh a randomized placebo-controlled single-blinded trial in 50 term neonates admitted within 6 hours of birth with moderate or severe perinatal asphyxia, classified according to Sarnat staging [30]. Infants were randomized to receive intravenous MgSO₄ at a dose of 250 mg/kg per dose, diluted in 20 mL of 5% dextrose and infused over 1 hour, repeated every 24 hours for three doses (n\u0026thinsp;=\u0026thinsp;25), or an equal-volume placebo consisting of normal saline infused in an identical manner (n\u0026thinsp;=\u0026thinsp;25), in addition to standard supportive care. No therapeutic hypothermia was administered. Outcomes included short-term neurological recovery parameters, cranial ultrasonography, EEG findings, serum MgSO₄ concentrations, and safety measures. MgSO₄-treated infants with moderate HIE demonstrated significantly earlier seizure control, faster normalization of cry and activity, earlier establishment of full oral feeding, and shorter hospital stay compared with placebo, whereas no statistically significant benefit was observed in infants with severe HIE. Neuroimaging and EEG findings at day 14 did not differ between groups, and no significant hemodynamic adverse effects were reported. Overall, postnatal MgSO₄ is safe and may improve short-term neurological recovery in moderate, but not severe, hypoxic-ischemic encephalopathy, without demonstrated effects on imaging or mortality. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAbdel-Aziz et al. (2021)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e \u003c/sup\u003e conducted in Egypt a randomized controlled open-label trial including 36 term and near-term neonates with moderate-to-severe HIE (defined by 5-min Apgar\u0026thinsp;\u0026le;\u0026thinsp;5, ventilation at 10 min, pH\u0026thinsp;\u0026lt;\u0026thinsp;7.1/base deficit\u0026thinsp;\u0026ge;\u0026thinsp;16, or pre-delivery fetal distress signs), allocated equally into three groups: whole-body therapeutic hypothermia (TH) alone (n\u0026thinsp;=\u0026thinsp;12), TH combined with MgSO₄ (n\u0026thinsp;=\u0026thinsp;12), or supportive care only (n\u0026thinsp;=\u0026thinsp;12). Cooling was initiated within 6 hours of birth and maintained for 72 hours. The adjunctive MgSO₄ regimen consisted of intravenous MgSO₄ at a dose of 250 mg/kg administered over 1 hour, once daily for three consecutive days, alongside dopamine infusion (5 \u0026micro;g/kg/min). Outcomes included short-term clinical measures (seizure frequency, duration of respiratory support, time to enteral feeding), neurological scores, and brain MRI findings. Infants treated with TH plus MgSO₄ demonstrated significantly fewer seizures, shorter respiratory support duration, earlier initiation of feeding, and more favorable short-term clinical outcomes compared with TH alone or supportive care, without safety concerns. Overall, MgSO₄ may provide additive short-term neuroprotective benefit when used as an adjunct to therapeutic hypothermia. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eIqbal et al. (2021)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e \u003c/sup\u003e conducted in Pakistan a prospective double-blind randomized controlled trial including 62 term or near-term neonates (\u0026gt;\u0026thinsp;35 weeks\u0026rsquo; gestation) with moderate-to-severe HIE (defined by inability to initiate or sustain breathing at birth with clinical encephalopathy features or seizures), admitted within 24 hours of birth. Infants were randomized to receive intravenous MgSO₄ at a dose of 250 mg/kg per dose, diluted to a volume of 3 mL/kg and infused over one hour, repeated at 24 and 48 hours (n\u0026thinsp;=\u0026thinsp;31), or an equal-volume placebo consisting of 10% dextrose infused in an identical schedule (n\u0026thinsp;=\u0026thinsp;31), in addition to standard supportive care. No therapeutic hypothermia was administered. Short-term outcomes included seizure control, time to initiation of feeding, duration of hospitalization, cranial ultrasonography findings, and mortality at discharge, while long-term outcome was assessed at six months using the ShaMaq Developmental Inventory. MgSO₄-treated infants demonstrated significantly earlier seizure control, earlier initiation of feeding, and shorter hospital stay compared with controls, without significant differences in cranial ultrasound abnormalities or mortality. At six months, no statistically significant improvement in neurodevelopmental outcome was observed. Overall, postnatal MgSO₄ improved short-term neurological recovery but did not confer measurable long-term neurodevelopmental benefit at six months. No clinical neurodevelopmental follow-up beyond 6 months was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSiddiqui et al (2021)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e \u003c/sup\u003e conducted in Pakistan a single-blinded RCT in which a repeated-dose regimen of MgSO₄ 250 mg/kg at 0, 24, and 48 hours was given to term neonates with HIE (defined by need for resuscitation at birth, with 1-min Apgar\u0026thinsp;\u0026le;\u0026thinsp;3 and 5-min Apgar\u0026thinsp;\u0026le;\u0026thinsp;7), diagnosed within 6 h of birth. Significant differences were reported in favor of MgSO₄ in terms of improved feeding, reduced seizure duration, and better neurological status at discharge. No long-term clinical neurodevelopmental assessment was reported.\u003c/p\u003e \u003cp\u003e \u003cb\u003eKhan et al. (2022)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e \u003c/sup\u003e conducted in Pakistan a prospective observational open-label study in a single tertiary neonatal unit in Pakistan, including 90 term neonates with moderate HIE (defined by 5-min Apgar score\u0026thinsp;\u0026lt;\u0026thinsp;5, umbilical blood pH\u0026thinsp;\u0026lt;\u0026thinsp;7.0, and clinical moderate HIE by Sarant staging). Neonates were randomly assigned to receive either combined therapy with MgSO₄ and melatonin (group 1; n\u0026thinsp;=\u0026thinsp;45) or melatonin alone (group 2; n\u0026thinsp;=\u0026thinsp;45). The intervention consisted of intravenous MgSO₄ at a dose of 250 mg/kg infused over 60 minutes on days 0, 1, and 3, in addition to enteral melatonin 10 mg/kg daily for five consecutive days; the comparator group received melatonin only. No therapeutic hypothermia was administered. Outcomes included serial arterial blood gas pH measurements, serum MgSO₄ concentrations, mortality, seizures, hypotension, renal failure, thrombocytopenia, and intracranial hemorrhage. The combination therapy group demonstrated significantly greater improvement in blood pH and higher serum MgSO₄ concentrations at days 3 and 7, as well as lower mortality compared with melatonin alone, while adverse event rates did not differ significantly between groups. Overall, MgSO₄ as adjunctive therapy to melatonin was associated with improved short-term clinical outcomes in neonates with HIE. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eNanda et al. (2022)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e \u003c/sup\u003e conducted in India a non-blinded randomized controlled trial including 227 neonates with moderate-to-severe perinatal asphyxia, admitted to a tertiary neonatal unit and randomized to receive intravenous MgSO₄ (n\u0026thinsp;=\u0026thinsp;116) or standard care alone (n\u0026thinsp;=\u0026thinsp;111). Eligible infants met clinical criteria for perinatal asphyxia (defined by 1-min Apgar\u0026thinsp;\u0026lt;\u0026thinsp;3 or 5-min Apgar\u0026thinsp;\u0026lt;\u0026thinsp;7, or moderate/severe encephalopathy within 24h with delayed cry) and were enrolled at admission; congenital anomalies and metabolic disorders were excluded. The intervention consisted of a loading dose of MgSO₄ 250 mg/kg infused over 1 hour in 20 mL of 5% dextrose at admission, followed by identical doses at 24 and 48 hours, in addition to standard supportive care. No therapeutic hypothermia was administered. Primary outcomes included seizure burden and anticonvulsant requirements, while secondary outcomes encompassed feeding patterns, duration of hospitalization, need for inotropic support, discharge status, and mortality; subgroup analyses were performed according to age at treatment initiation (\u0026lt;\u0026thinsp;6 h, 6\u0026ndash;24 h, \u0026gt;\u0026thinsp;24 h). MgSO₄-treated infants demonstrated significantly earlier initiation and achievement of full feeds, reduced seizure frequency and antiepileptic drug requirements, lower need for inotropes, shorter hospital stays, and higher discharge rates, with the greatest benefit observed when treatment was initiated within 6 hours of life. No significant adverse hemodynamic or biochemical effects were reported. Overall, early postnatal intravenous MgSO₄ is safe and associated with improved short-term clinical outcomes in neonates with moderate-to-severe perinatal asphyxia, with efficacy appearing time-dependent. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eKumar et al (2023)\u003c/b\u003e \u003csup\u003e \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e \u003c/sup\u003e conducted in India a randomized controlled trial to determine whether adjunctive MgSO₄ provides additional neuroprotective benefit when combined with therapeutic hypothermia in term neonates with HIE (defined by pH\u0026thinsp;\u0026le;\u0026thinsp;7 / base deficit\u0026thinsp;\u0026ge;\u0026thinsp;12 within 1h, or 10-min Apgar\u0026thinsp;\u0026le;\u0026thinsp;5 / ventilation\u0026thinsp;\u0026ge;\u0026thinsp;10 min with acute perinatal event). Overall, 134 infants were randomized to receive intravenous MgSO₄ (250 mg/kg once daily for three days, initiated within six hours of birth) plus therapeutic hypothermia, or hypothermia alone. The primary endpoint was a composite of mortality and/or major neurodevelopmental disability at one year of age, assessed using the Developmental Assessment Scale for Indian Infants. Secondary outcomes included neurological status at discharge, and total serum antioxidant status, malondialdehyde, a marker of CNS damage, as well as acute adverse events (hypotension, respiratory depression). Among 115 infants included in the primary analysis, the composite outcome did not differ significantly between the MgSO₄ group (24%) and the control group (33%) (RR 0.72; 95% CI 0.40\u0026ndash;1.30; p\u0026thinsp;=\u0026thinsp;0.30). Secondary outcomes and adverse events were also comparable between groups. Kumar et al concluded that MgSO₄ does not provide additive neuroprotection in cooled term infants with HIE. No clinical neurodevelopmental follow-up was performed in this study.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eNarrative reviews (N\u0026thinsp;=\u0026thinsp;2)\u003c/span\u003e that appeared in our systematic search included the work of Muralidharan et al (2025)\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e that included all the studies already mentioned above. Additional narrative review of Whitelaw et al (2002)\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e summarized non-clinical study in piglets (Penrice, 1997)\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e and a phase I/ Pharmacokinetic study (Levene et al. (1995)\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. That work conducted a phase I physiological and pharmacokinetic non-randomized and non-blinded study in 15 term neonates with birth asphyxia (Apgar score\u0026thinsp;\u0026lt;\u0026thinsp;6 at 10 minutes), evaluated within 12 hours of delivery, to assess the acute effects of two different doses of intravenous MgSO₄. Seven infants received 400 mg/kg MgSO₄ and eight received 250 mg/kg MgSO₄, administered as a single intravenous infusion over 10\u0026ndash;30 minutes. Outcomes included serial measurements of serum MgSO₄ concentrations, mean arterial pressure, heart rate, respiratory function, muscle tone, and EEG activity. The higher dose (400 mg/kg) resulted in significant hypotension and prolonged respiratory depression, whereas the lower dose (250 mg/kg) achieved serum MgSO₄ concentrations within the putative neuroprotective range without hypotension, although transient respiratory depression occurred in one infant. EEG activity was not altered at either dose. Overall, 400 mg/kg MgSO₄ carries an unacceptable risk of hypotension, while 250 mg/kg appears physiologically safer, and proposed a multi-dose regimen (250 mg/kg followed by 125 mg/kg at 24 and 48 hours) for future neuroprotection trials.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eMeta-analyses\u003c/h2\u003e \u003cp\u003eWe attempted to group the various studies having similar entry criteria and design (in terms of magnesium administration protocol) and which reported similar outcomes. Three studies reported biochemical indices of brain injury: Khashaba et al. (2006)\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, El-Farargy et al. (2019)\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e and Nonomura et al. (2019)\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Overall, marked heterogeneity exists in marker type, biological matrix, sampling schedule, and clinical context, precluding statistical aggregation or meta-analysis. Thus, in terms of brain injury biochemical indices, no meta-analyses could be conducted, and we are left with the individual qualitative analysis of each one of them (as reported above).\u003c/p\u003e \u003cp\u003eNine studies had similar entry criteria and magnesium administration protocols. However, they did not report universally the same outcomes. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e depicts the various outcomes analyzed in the above-mentioned clinical trials. Meta-analyses were conducted on each outcome, based on the studies that reported these specific outcomes.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of outcomes reported across studies included in the meta-analysis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroenendaal 2002\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eKhashaba 2006\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBhat 2009\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHossain 2013\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRahman 2015\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSavitha 2016\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFiroz 2020\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSiddiqui 2021\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eIqbal 2021\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eMeta-analysis eligibility\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIn-hospital / pre-discharge mortality\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eEligible (primary)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSeizure control\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eEligible (secondary)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeurological status at discharge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eEligible (secondary)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTime to establish oral/enteral feeding\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eEligible (secondary)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEEG / aEEG abnormalities\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eaEEG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEEG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eEEG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNot eligible (heterogeneous modality)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeuroimaging abnormalities (CT/US)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eUS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eUS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNot eligible (timing/definition heterogeneous)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBiochemical markers\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNot eligible (non-clinical endpoints)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLong-term neurodevelopment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes (24 mo. Study interrupted)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eYes (6 mo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNot eligible (insufficient overlap)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eWe identified and analyzed 24 clinical trials evaluating postnatal MgSO₄ administration within the first 12 hours of life in neonates with encephalopathy. A previous systematic review published in this journal identified only five such trials, highlighting the substantial expansion of the evidence base. Most studies reported that after 3 doses of 250 mg MgSO₄, magnesium concentrations in blood reached levels considered to be neuroprotective in preterm infants (1.2\u0026ndash;3.77 mmol/L)\u003csup\u003e5,7,13,25,36\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAll the studies included were conducted in term populations. MgSO₄ administration was generally reported as safe across studies, with no clinically significant adverse effects on hemodynamic stability, respiratory function, or mortality. Most studies reported improved short-term outcomes in the MgSO₄ group, particularly with respect to seizure control, feeding, and neurological status at discharge. No study demonstrated worse outcomes with MgSO₄. When feasible, meta-analyses confirmed significant benefits in seizure occurrence, feeding establishment, and neurological status at discharge. However, no statistically significant effect on mortality was observed.\u003c/p\u003e \u003cp\u003eSeveral limitations warrant consideration.\u003c/p\u003e \u003cp\u003eFirst, substantial heterogeneity exists across studies in patient populations (including inconsistent and outdated definitions of neonatal asphyxia), study design (randomization and blinding), and outcome selection. Outcomes varied widely, encompassing both safety (e.g., mortality, hemodynamics, oxygenation) and efficacy endpoints (e.g., seizures, neurological status at discharge, feeding outcomes, and heterogeneous biochemical and imaging markers of brain injury).\u003c/p\u003e \u003cp\u003eSecond, most trials of postnatal MgSO₄ were conducted prior to the adoption of therapeutic hypothermia and predominantly in low- and middle-income settings. Only one study evaluated MgSO₄ as an adjunct to hypothermia, focusing primarily on safety rather than efficacy. Accordingly, the effect of MgSO₄ in the era of hypothermia remains largely unknown, and no large randomized controlled trials from high-resource settings have addressed this question. Existing evidence is therefore mainly applicable to contexts in which hypothermia is unavailable. Nevertheless, given its low cost and accessibility, MgSO₄ may represent a pragmatic alternative where hypothermia cannot be implemented.\u003c/p\u003e \u003cp\u003eThird, long-term neurodevelopmental data are scarce. Only one study reported structured outcomes at 6 months, with no significant between-group differences. No conclusions can therefore be drawn regarding sustained neurodevelopmental benefit.\u003c/p\u003e \u003cp\u003eFourth, evidence on MgSO₄-associated neuroprotection based on biochemical markers remains fragmented. Future studies require standardized biomarker selection, consistent timing of measurements, and integration with neuroimaging to enable mechanistic interpretation and comparability across studies.\u003c/p\u003e \u003cp\u003eFifth, despite strong evidence supporting antenatal MgSO₄ for neuroprotection in preterm infants, no randomized double-blind trials have evaluated early postnatal administration in this population. This gap is particularly relevant for preterm neonates following precipitous deliveries without antenatal exposure and represents a priority for future research.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003ePostnatal MgSO₄ appears safe and is consistently associated with improved short-term clinical outcomes in neonates with HIE, particularly in seizure control, neurological status at discharge, and feeding establishment. However, no significant reduction in mortality has been demonstrated, and evidence regarding long-term neurodevelopmental benefit remains extremely limited. Most available data derive from pre-hypothermia-era studies or settings where therapeutic hypothermia is not routinely available. Consequently, the role of MgSO₄ as an adjunct to hypothermia remains uncertain. Its definitive clinical value requires confirmation through adequately powered trials with standardized protocols and long-term follow-up.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePolicy Implications Based on the Main Findings\u003c/h2\u003e \u003cp\u003eBased on the synthesis of the available evidence, policy considerations should be structured according to three distinct neonatal populations, reflecting differences in resource availability, current standards of care, and biological vulnerability.\u003c/p\u003e \u003cp\u003e \u003cb\u003e1. Term infants born in high-income countries where therapeutic hypothermia is available\u003c/b\u003e \u003c/p\u003e \u003cp\u003eIn term infants with moderate-to-severe neonatal encephalopathy treated in developed healthcare systems where therapeutic hypothermia is standard of care, postnatal MgSO₄ appears safe and is consistently associated with improved short-term outcomes, particularly in seizure control, neurological examination at discharge, and establishment of oral feeding. However, there is no convincing evidence of reduced mortality, and there is essentially no robust evidence regarding long-term neurodevelopmental outcomes, especially when MgSO₄ is administered in conjunction with hypothermia.\u003c/p\u003e \u003cp\u003eFrom a policy perspective, MgSO₄ should not be adopted as routine adjunctive therapy alongside hypothermia outside the framework of adequately powered randomized controlled trials with predefined long-term neurodevelopmental endpoints. In these settings, its role remains investigational, and future research must specifically assess whether magnesium provides incremental benefit beyond established cooling protocols.\u003c/p\u003e \u003cp\u003e \u003cb\u003e2. Term infants born in low- and middle-income countries where therapeutic hypothermia is not available\u003c/b\u003e \u003c/p\u003e \u003cp\u003eIn settings where therapeutic hypothermia is unavailable or inconsistently implemented, there is no evidence regarding both short and long term outcomes of infants born with perinatal asphyxia, and standards of neuroprotective care are often variable.\u003c/p\u003e \u003cp\u003eImportantly, only one study addressed the safety of MgSO₄ administration in conjunction with hypothermia, and it focused primarily on safety rather than efficacy outcomes. Therefore, in countries where cooling is not part of routine care, policymakers should carefully consider whether MgSO₄ loading or structured administration could be incorporated into standardized protocols. Any such implementation should ideally occur within prospective registries or pragmatic trials designed to generate high-quality data on both safety and clinically meaningful outcomes.\u003c/p\u003e \u003cp\u003e \u003cb\u003e3. Preterm infants\u003c/b\u003e \u003c/p\u003e \u003cp\u003eTherapeutic hypothermia is currently contraindicated in preterm infants because of safety concerns and lack of supporting evidence. At the same time, no randomized controlled trials have evaluated early postnatal MgSO₄ specifically in preterm neonates with hypoxic-ischemic injury. This represents a critical knowledge gap. The question is particularly relevant in cases of abrupt placental abruption or precipitous delivery, where antenatal MgSO₄ could not be administered and hypothermia is not an option.\u003c/p\u003e \u003cp\u003eIn this population, evaluation of MgSO₄ as a potential neuroprotective intervention warrants careful investigation through dose-finding and safety trials before any policy recommendations can be made. Until such data are available, routine postnatal magnesium use in preterm infants cannot be recommended.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eOverall Policy Direction\u003c/h2\u003e \u003cp\u003eAcross all populations, the consistent safety profile of postnatal MgSO₄ supports continued scientific evaluation. However, the absence of robust long-term neurodevelopmental data precludes definitive policy endorsement. Future studies must be multicenter, adequately powered, and include standardized dosing regimens, harmonized short-term outcomes, and mandatory long-term follow-up beyond infancy. Only through such rigorous investigation can the true role of postnatal MgSO₄ in neonatal encephalopathy be clarified and translated into evidence-based policy.\u003c/p\u003e \u003c/div\u003e "},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eneonatal encephalopathy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHIE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehypoxic-ischemic encephalopathy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMgSO₄\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emagnesium sulfate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eaEEG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eamplitude-integrated electroencephalography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRCTs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erandomized controlled trials\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCSF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecerebrospinal fluid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emagnetic resonance imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erelative risk\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e The authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials:\u0026nbsp;\u003c/strong\u003eThe data supporting the findings of this study are available within the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement:\u0026nbsp;\u003c/strong\u003eNone to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, F.B.M. and Y.D.; methodology, F.B.M. and Y.D.; formal analysis, Y.D.; investigation, Y.D. and F.B.M.; data curation, Y.D.; writing- original draft preparation, Y.D.; writing- review and editing, F.B.M., I.A., and J.M.; supervision, F.B.M. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement:\u003c/strong\u003e Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eShankaran S. Therapeutic hypothermia for neonatal encephalopathy. Curr Opin Pediatr 2015;27:152\u0026ndash;157.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJacobs SE, Berg M, Hunt R, et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013;1:CD003311.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChollat C, Sentilhes L, Marret S. Fetal neuroprotection by magnesium sulfate. Front Neurol 2018;9:247.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShepherd ES, Goldsmith S, Doyle LW, et al. Magnesium sulphate for women at risk of preterm birth. Cochrane Database Syst Rev 2024;5:CD004661.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGroenendaal F, Rademaker CM, Toet MC, de Vries LS. Effects of magnesium sulphate on EEG. Acta Paediatr 2002;91:1073\u0026ndash;1077.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIchiba H, Tamai H, Negishi H, et al. Magnesium sulfate infusion for birth asphyxia. Pediatr Int 2002;44:505\u0026ndash;509.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhat MA, Charoo BA, Bhat JI, et al. Magnesium sulfate in perinatal asphyxia. Pediatrics 2009;123:e764-e769.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePage MJ, McKenzie JE, Bossuyt PM, et al. PRISMA 2020 statement. BMJ 2021;372:n71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTagin M, Shah PS, Lee KS. Magnesium for neonatal encephalopathy. J Perinatol 2013;33:663\u0026ndash;669.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGowda BB, Rath C, Muthusamy S, et al. Magnesium sulfate outcomes meta-analysis. J Pediatr 2023;262:113610.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFei Q, Wang D, Yuan T. Adjuvant therapies for hypothermia. Indian J Pediatr 2024;91:235\u0026ndash;241.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang M, Wang K, Liu B, et al. Hypoxic-ischemic encephalopathy therapies. Mol Neurobiol 2025;62:2105\u0026ndash;2122.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGathwala G, Khera A, Singh I. Magnesium therapy in asphyxia. Indian J Pediatr 2006;73:209\u0026ndash;212.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhashaba MT, Shouman BO, Shaltout AA, et al. Magnesium in neonatal asphyxia. Brain Dev 2006;28:375\u0026ndash;379.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGathwala G, Khera A, Singh J, et al. Magnesium neuroprotection. J Pediatr Neurosci 2010;5:102\u0026ndash;104.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHossain M, Mannan M, Yeasmin F, et al. Magnesium sulfate outcome. Mymensingh Med J 2013;22:727\u0026ndash;735.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDixon BJ, Reis C, Ho WM, et al. Neuroprotection after HIE. Int J Mol Sci 2015;16:22368\u0026ndash;22401.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahmood T, Zulfiqar R, Farah T, et al. Magnesium sulfate outcomes. J Rawalpindi Med Coll 2015;19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRahman SU, Canpolat FE, Oncel MY, et al. Mag Cool study. J Clin Neonatol 2015;4:158\u0026ndash;163.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRashid A, Fatima N, Asim M, et al. Magnesium sulphate outcome. Pak Postgrad Med J 2015;26:2\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAhmed FKR, Sultana NS. Safety of magnesium sulphate. Int J Contemp Pediatr 2016;3:80\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSavitha M, Rajprakash R. Magnesium sulphate effect. Int J Contemp Pediatr 2016;3:150\u0026ndash;154.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSreenivasa B, Lokeshwari K, Joseph N. Magnesium sulphate complications. Sri Lanka J Child Health 2017;46:148.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGulczynska E, Gadzinowski J, Nowiczewski M, et al. Hypothermia plus magnesium feasibility. Neonat Pediatr Med 2018;4:165.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEl-Farargy M, Soliman N. Magnesium sulfate and melatonin trial. J Neonatal Perinatal Med 2019;12:379\u0026ndash;384.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSarnat HB, Sarnat M. Neonatal encephalopathy. Arch Neurol 1976;33:696\u0026ndash;705.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNonomura M, Harada S, Asada Y, et al. Combination therapy HIE. BMC Pediatr 2019;19:13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFiroz MMR. Magnesium sulphate effectiveness. ARC J Pediatr 2020;7:6\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbdel-Aziz SM, Abdel Rahman MSM, Shoreit AH, et al. Cooling and magnesium outcome. J Child Sci 2021;11:e280-e286.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIqbal N, Younus J, Malik M, et al. Magnesium sulfate efficacy. Cureus 2021;13:e16826.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiddiqui MA, Butt TK. Magnesium sulphate role. J Coll Physicians Surg Pak 2021;31:817\u0026ndash;820.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhan MH, Ann Q, Khan MS, et al. Magnesium with melatonin. Cureus 2022;14:e21163.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNanda AK, Jalan A, Pradhan SK, et al. Magnesium infusion outcomes. Int J Health Sci 2022;6:13064\u0026ndash;13075.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKumar C, Adhisivam B, Bobby Z, et al. Magnesium adjunct therapy. Indian J Pediatr 2023;90:886\u0026ndash;892.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMuralidharan O, Rehman S, Sihota D, et al. Post-asphyxial care. Neonatology 2025;122:84\u0026ndash;105.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWhitelaw A, Thoresen M. Clinical trials after asphyxia. Curr Opin Pediatr 2002;14:664\u0026ndash;668.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePenrice J, Amess PN, Punwani S, et al. Magnesium and cerebral energy failure. Pediatr Res 1997;41:443\u0026ndash;447.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevene MI, Blennow M, Whitelaw A, et al. Magnesium dosing effects. Arch Dis Child Fetal Neonatal Ed 1995;73:F174-F177.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"magnesium sulfate, neonatal encephalopathy, neuroprotection, hypoxic-ischemic encephalopathy, neonatal hypoxia","lastPublishedDoi":"10.21203/rs.3.rs-9362928/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9362928/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eObjective:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTo evaluate the safety and efficacy of postnatal magnesium sulfate (MgSO₄) for neuroprotection in neonates with neonatal encephalopathy (NE).\u003c/p\u003e\u003cp\u003e\u003cb\u003eStudy design:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eSystematic review and meta-analysis of controlled clinical trials assessing MgSO₄ administered within 12 hours of birth in term or near-term infants with NE. Databases searched included MEDLINE, Embase, and Cochrane sources.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTwenty-four trials were included. MgSO₄ was consistently safe, with no significant adverse hemodynamic or respiratory effects. Meta-analyses demonstrated improved short-term outcomes, including reduced seizure occurrence, improved neurological status at discharge, and earlier establishment of feeding. No significant reduction in mortality was observed. Evidence regarding long-term neurodevelopmental outcomes was extremely limited. Data on MgSO₄ use alongside therapeutic hypothermia were scarce and inconclusive.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion:\u003c/b\u003e\u003c/p\u003e \u003cp\u003ePostnatal MgSO₄ is safe and associated with improved short-term clinical outcomes in neonates with NE. However, absence of long-term benefit and limited evidence in the era of therapeutic hypothermia preclude routine clinical use.\u003c/p\u003e","manuscriptTitle":"Magnesium Sulfate for Brain Protection in Neonatal Encephalopathy: A Systematic Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-28 00:22:52","doi":"10.21203/rs.3.rs-9362928/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2026-05-08T13:05:16+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-05T23:31:29+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-04T05:51:24+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-04-23T11:26:39+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-04-19T17:39:37+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2026-04-19T15:16:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-14T18:53:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Perinatology","date":"2026-04-14T14:07:05+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2026-04-13T11:01:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-09T04:06:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f2dbdebb-a090-46ee-ae81-8f896f2f0922","owner":[],"postedDate":"April 28th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"revise","date":"2026-05-08T13:05:16+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-05T23:31:29+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-04T05:51:24+00:00","index":1,"fulltext":"This content is not available."}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":67109669,"name":"Health sciences/Diseases/Neurological disorders/Paediatric neurological disorders"},{"id":67109670,"name":"Health sciences/Health care/Paediatrics"}],"tags":[],"updatedAt":"2026-05-12T18:15:49+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-28 00:22:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9362928","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9362928","identity":"rs-9362928","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}