Effect of Intravenous Magnesium Sulphate on in-Hospital Mortality in Neonates with Perinatal Asphyxia: A Prospective Cohort Study

Background: Early neonatal deaths in Pakistan account for 7% of global neonatal mortality rate, with perinatal asphyxia being responsible for 23% of these cases. Controversy exists in the literature regarding role of magnesium sulphate administration on reducing in-hospital mortality in newborns with perinatal asphyxia. Objectives: To determine the effect of intravenous magnesium sulphate on in-hospital mortality in neonates with perinatal asphyxia. Methods: This prospective cohort study was conducted at the Department of Pediatric Medicine, Nishtar Hospital Multan over a period of six months from January 2022 to June 2022. A total of 183 consecutive full-term neonates, weighing ≥ 2500 grams, with Apgar score < 7 at 5-minutes after birth, presenting within 48-hours of life were included in the study. Neonates presenting within 6-hours after birth received intravenous magnesium sulphate (MgSO ) – exposed group and neonates presenting after 6-hours did not get MgSO – 4 4 unexposed group. Baseline characteristics and survival outcome was recorded. Binary logistic regression analysis was run and Kaplan-Meier survival curve is constructed for the assessment of mortality. Results: There were 90 neonates in exposed group and 93 in unexposed group. Males constituted 53% of the study population. Overall mortality rate was 15.8% (n=29). Severe asphyxia (RR 8.5, 95% CI 4.0 – 18.0; p < 0.001) and spontaneous vaginal delivery (RR 1.8, 95% CI 1.1 – 2.9; p = 0.02) were the independent predictors of mortality. Mortality (7.8% vs. 23.6%, p-value 0.003) was significantly higher in unexposed group compared to exposed group. In exposed group the median survival time was 16 days (95% CI-8.7 – 23.3) 2 compared to 11 days (95% CI 9.9 – 12.0) in unexposed group (Log-rank test: χ = 6.03, df -1, p = 0.01). Conclusion: Magnesium sulphate was effective in lowering neonatal mortality due to moderate-severe perinatal asphyxia. In order to further validate its impact on mortality, multi-center studies are suggested.


Introduction
E ach year four million children die in their first 28 days of life, and perinatal asphyxia is the second 1 most frequent reason.Early neonatal deaths in Pakistan account for 7% of global neonatal mortality rate, with perinatal asphyxia being responsible for 23% of these Perinatal asphyxia results in Hypoxic Ischemic Encephalopathy (HIE).As asphyxia becomes more severe, there is a corresponding rise in morbidity and death.Nearly all patients with severe HIE and 50-60% of children with mild HIE have neuro developmental 4 abnormalities.
The principal excitatory amino acid neurotransmitter glutamate, released in greater amounts into the extracellular compartment of the brain after fetal hypoxia, causes multi-organ failure.The other organs may recover, 5 but the brain is permanently injured.High glutamate concentration causes NMDA (N-methyl-D-aspartate) channels to open, enabling an excessive amount of calcium to enter the neurons and resulting in permanent neuronal damage.Since magnesium is a naturally occurring NMDA receptor antagonist, it protects the deve-6 loping brain from harm brought on by glutamate.Antiexcitotoxic (blocks the NMDA receptor), antioxidant (needed for glutathione biosynthesis), anti-cytokine (decreases levels of inflammatory cytokines), and antiplatelet (decreases platelet aggregation) effects are some of the mechanisms used in experimental work to support

7,8
the potential role of magnesium sulphate.The intravenous infusion of magnesium after a simulated hypoxic ischemic injury prevents neurological impairment in 9 several animal models.As a result, magnesium sulphate is recommended for usage in clinical settings to prevent brain damage and glutamate excitotoxicity.Studies on postnatal magnesium treatment for infants who had asphyxia at birth have shown some benefits while sho-

10,11
wing no benefits in others.
The purpose of the current study was to ascertain the impact of intravenous magnesium sulphate treatment on the in-hospital mortality of asphyxiated term newborns.

Methodology
This prospective cohort study was conducted over a period of six months from January, 2022 to June 2022 at Department of Pediatric Medicine Nishtar Hospital Multan, Pakistan after approval from institutional ethics committee (ERC#1163).Neonates with Apgar score < 7 at 5-minutes after birth and requiring active resuscitation were clinically categorized into mild, moderate and severe perinatal asphyxia based on Sarnat and Sarnat 12 staging.A total of 183 consecutive full-term neonates weighing ≥ 2500 grams with moderate to severe perinatal asphyxia presenting within 48-hours of life were enrolled in the study after informed consent provided by the parents.Neonates with congenital heart diseases (other than patent ductus arteriosus), with syndromic features and with C-reactive protein >6 (neonatal sepsis) were excluded.Baseline characteristics including age, gender, gestational age, mode of delivery, birth weight and severity of perinatal asphyxia was noted.According to hospital protocol for the management of perinatal asphyxia neonates presenting within 6-hours after birth were given intravenous MgSO , three doses 250 mg/kg/ 4 dose, 24 hours apart (exposed group).Neonates presenting after 6-hours of birth did not get intravenous MgSO 4 (un-exposed group) but were provided with routine neonatal care (oxygen, intravenous fluid, correction of electrolyte imbalance, prevention and treatment of seizures and complications of perinatal asphyxia and consideration of orogastric feeding if child is able to tolerate).The outcome was assessed in terms of inhospital mortality, time to establishment of full oral feeding and duration of hospital stay.
A sample size of 183 neonates with perinatal asphyxia was calculated considering mortality rate of 35% in 13 unexposed neonates as reported by Siddiqui MA et al , and expected mortality of 15% in exposed neonates with power of 80%, confidence level of 95% and attrition rate of 10%.The data was analyzed using STATA 12.0.Descriptive statics were run for numerical and categorical data.Comparison between exposed and un-exposed groups were through independent sample t-test and chi-square test for numerical and categorical data respectively.Unadjusted and adjusted binary logistic regression analysis were run for the assessment of risk factors for mortality between the two groups.A p-value of ≤0.20 was considered significant at bivariate level and ≤ 0.05 at multivariable level.Relative risk with 95% confidence interval is reported.The goodness of fit for the adjusted model was ascertained through the Hosmer-Lemeshow test.Kaplan-Meier method is used to construct the survival curves and mortality between neonates treated with and without MgSO was compared 4 through log-rank test.

Results
Mean gestational age was 38.1 ± 0.9 weeks and post-natal age was 19.6 ± 16.7 hours.Males constituted 53% (n=97) of the study population and 54.6% (n=100) were delivered through cesarean section.Mean birth weight of the neonates was 3.1 ± 0.4 kg and 71.6% (n=131) suffered from moderate perinatal asphyxia.Mean time to start oral feeding was 5.2 ± 1.9 days, inotropes were used in 21.8% (n=40) and mean hospital stay was 6.5 ± 2.6 days.Overall mortality rate was 15.8% (n=29).Ninety neonates were received within six hours after birth and were given intravenous MgSO and 93 neo-4 nates were received after this duration did not get MgSO 4 [Table 1].
Distribution of gender, gestational age, mode of delivery, birth weight and severity of perinatal asphyxia did not differ significantly between exposed and unexposed groups.Nevertheless, use of inotropes (67.5% vs. 32.5%,p-value 0.01) was higher in exposed group.Mortality (7.8% vs. 23.6%,p-value 0.003) was significantly higher in unexposed group compared to exposed group.Similarly, mean time to start oral feed (4.4 ± 1.9 vs. 6.2 ± 1.5 days) and hospital stay (5.8 ± 3.1 vs. 7.2 ± 1.8) were significantly (p-value< 0.001) low in exposed group compared to unexposed group respectively [Table 1].
Most of the demographic characteristics were comparable in expired and alive neonates.However, proportion of severe asphyxia was significantly high in neonates who expired (75.9% vs. 19.5%)compared to alive neonates.On the other hand, proportion of neonates reaching hospital within 6-hours of delivery was higher in surviving neonates (53.8% vs. 24.1%)compared to neonates who expired [Table S1].

Figure-1: The Kaplan-Meier survival estimates of neonates with perinatal asphyxia (N=183)
In the unadjusted model it is evident that the risk of mortality was three times higher in unexposed group, 7.9 times in neonates with severe asphyxia, 1.    who have had perinatal asphyxia.
Following the earliest primary neuronal injury, when oxygen and glucose supply to brain is interrupted, there is a latent period of up to six hours before a secondary phase of injury starts.This is the period when the injured area is re-perfused, and damaged cells are lysed, releasing toxic neurotransmitters.The goal of magnesium sulphate therapy is to intervene during the latent period Hypothermia (selective or whole body) is current standard of care for neonates with perinatal asphyxia.This treatment modality could not be provided to our patients due to lack of proper equipment and expertise in using locally improvised methods of cooling.Other limitations are lack of long-term follow-up for the assessment of neurological and developmental outcomes in surviving newborn, lack of randomization and inability to compare exposed vs un-exposed group within 6 hours of life.Mode of delivery was comparable in both the surviving and expired neonates but we did not have data on perinatal factors like duration of labour, obstructed labour, neonatal resuscitation and premature rupture of membrane.

Conclusion
Postnatal magnesium sulfate infusion, when given within 6 hours, is not only effective in reducing the mortality but it also reduces mean time to start oral feeding and hospital stay for neonates with moderate to severe perinatal asphyxia.More studies with large sample sizes, longer follow-up period and preferably multicenter trials, are required to validate these results.

Table S1 :
Comparison of characteristics between neonates with perinatal asphyxia who survived and expired (N=183)an overall mortality rate of 26%.They found that at the time of discharge, experimental group was receiving more (78% vs. 44%) oral feeds compared with the control group.Concordant to our results, another study from Pakistan reported mortality rate of 13% in treat- 20and reduce damage from the secondary neuronal injury.10physiological changes including mean arterial pressure.Severe perinatal asphyxia was the independent risk factor of mortality in our study.More then half of the neonates received MgSO yet the mortality rate in severe 4 asphyxia was 42.3% (n/N=22/52).This finding indicated that MgSO could not provide much benefit to neo-4 nates with severe asphyxia.This is supported by another 27 study from Bangladesh where mortality rate in severe perinatal asphyxia was comparable between MgSO 4 treated and placebo group (50% vs. 55.5%).