Perinatal asphyxia is a condition where hypoxaemia and acidosis are present in the foetus or the newborn infants. It is a failure newborn to initiate spontaneous, sustained, and vigorous respiration effort at birth. It is also defined as a failure to initiate spontaneous respirations and/or a 5-minute Apgar score of less than 7: the most commonly used indicator in the identification of birth asphyxia in resource limited settings [1] . Perinatal asphyxia is one of the leading causes of perinatal death and a recognized cause of neuromotor disability among survivors [2] . About 20% - 30% of asphyxiated newborns who develop hypoxic ischemic encephalopathy (HIE) die during the neonatal period, and one third to one half of survivors are left with cerebral palsy and mental retardation [3] [4] . Survivors present with several short and long term morbidities, including: seizure disorders, tone abnormalities, feeding difficulties, delayed developmental milestones, learning difficulties, cerebral palsy and mental retardation. The morbidities increase with asphyxia severity. The frequency of severe perinatal asphyxia complications, hypoxic ischemic encephalopathy (HIE) and incidence of up to 26.5/1000 live births is unacceptably high despite advances in perinatal care [5] [6] . Encephalopathy occurs in 50% to 60% of patients with severe perinatal asphyxia. Among patients with moderate HIE, 10% to 20% die, and 30% to 40% develop neurodevelopmental disorders, whereas 50% of patients with severe HIE die and almost all survivors develop neurodevelopmental deficits [7] [8] [9] .

According to Onyearugha et al. [10] , findings in some studies in Nigeria reported a prevalence of severe perinatal asphyxia between 46 - 63/1000 live births, and this is unacceptably high. The prevalence of severe birth asphyxia in any community is to a large extent dependent on prevailing risk factors, these in turn being influenced by the extent and impact of health education, literacy level, women empowerment, cultural and traditional beliefs affecting efficient utilization of health care services as well as the quality of antenatal, obstetric and neonatal care. Other factors including poverty, ignorance, poor communication network, harmful traditional and cultural practices with significant negative effect on utilization of appropriate health care services by women in pregnancy and labour are particularly rife in the developing countries like Nigeria [9] [10] .

Neuro-science research has revealed our understanding of the mechanisms by perinatal asphyxia neuronal damage and adverse consequences. Asphyxia leads to two types of cerebral injuries: the primary neuronal injury that occurs at the time of hypoxic-ischemic insults and the secondary cerebral injury that occurs over hours to days after accumulation of excessive intra-neuronal calcium through stimulation of the excitatory N-methyl-D-aspartate (NMDA) glutamate receptors, which triggers apoptosis of the affected neurons [2] .

Magnesium is a naturally occurring NMDA receptor antagonist that blocks neuronal influx of calcium within the ion channels. This block is voltage-dependent and is overcome during axonal depolarization that occurs in hypoxic-ischemic insults. If the extra-cellular magnesium concentration is increased, this blockade can be restored. Finding from earlier studies regarding the effects of magnesium sulphate after stimulated hypoxic-ischemic insults in several animal models revealed neuro-protective effects after administration of intravenous magnesium sulphate at a dose of 250 mg/kg daily at 24 hours interval within the first three days of delivery preferably of severely asphyxiated newborn [11] [12] . Magnesium sulphate may also have direct actions on mitochondrial activity, anticonvulsant properties and haemodynamic effects by increasing cerebral blood flow. Some data also suggest that MgSO₄ may serve an anti-apoptotic role and prevent neuronal cell loss [13] [14] [15] . Magnesium sulphate has wider use in critical care especially by Obstetrician in labour as tocolytic agents and for the suppression of pregnancy induced hypertension and has shown to be beneficial in neonates of treated mothers [7] . However, there is scanty work regarding the role of magnesium sulphate in severely asphyxiated newborn and even the few trials done are not widely circulated thus limiting knowledge and experience on its potential neuroprotective effects. We conducted this interventional trial to assess the potential neuroprotective effect of magnesium sulphate in treating severely asphyxiated newborns and improvement of the neurological outcome.

Perinatal asphyxia especially the severe form is a common problem and contributes significantly to neonatal morbidity and mortality. Encephalopathy occurs in 50% to 60% of patients with severe perinatal asphyxia. Patients with moderate HIE 10% to 20% die and 30% to 40% develop neurodeficits, whereas 50% of patients with severe HIE die and almost all survivors develop neurodeficits. Magnesium sulphate administration to severely asphyxiated neonate prevent the complication associated with hypoxic-ischemic encephalopathy, so there is need to carry this study so as to encourage its wide application in affected neonates.

1) General aim: To determine the benefit of magnesium sulphate on perinatal asphyxia in neonates presenting UMTH Maiduguri North-Eastern Nigeria.

2) Specific objective:

a) Determine the effect of magnesium sulphate on neurological outcome in severe perinatal Asphyxia.

b) Determine the effect of magnesium sulphate on commencement of oral feed.

c) Determine the effect of magnesium sulphate on reduction of duration of Admission/hospitalization.

During the period of the study (1^st August 2017 to 31^st July 2018), a total of 52 patients were randomly recruited, comprising of 34 (65.4%) male and 18 (34.6%) males, with majority (82.7%) weighing ≥ 2500 g at birth. Most (96.2%) of patient were term baby (GA ≥ 37 weeks). Most (90.4%) were in-hospital born, vaginal delivery accounted for 55.8% and 44.2% assisted delivery respectively. About one half (55.8%) of the patients commenced MgSO₄ therapy at < 6 hours after birth, while 30.6% and 16.6% commenced MgSO₄ therapy at 6 - < 24 hours and >24 hours after birth respectively. Majority (73.1%) of the mothers were booked and most were booked in either PHC (18.5%), General hospital (14.8%) or tertiary hospital (33.3%). About 58% were primiparous, while 17 (32.7%) and 5 (9.6%) was multipara and grand multipara respectively. The percentage of mothers who did not had prenatal MgSO₄ and those who had prenatal MgSO₄ was approximately 88.5% and 11.5% respectively while 25 (48.1%) of the mothers presented with either preeclampsia or eclampsia. Only 14 (26.9%) of the mothers had antepartum haemorrhage.

Table 1 indicates an unadjusted analysis of factors predicting survival outcome of neonatal asphyxia treated with MgSO₄. It largely assessed features like Sex, birth weight, time of first MgSO₄ dose, gestation age, place of delivery, mode of delivery, anticonvulsant administration, and antibiotic-use showed no significant association with survival without neurological deficit. However, time to commencement of first enteral feeding (p = 0.018) and time to full enteral feeding (p = 0.015) showed significant correlation with the survival without neurological deficit (Table 1). When compared with patients who commenced enteral feeding after 7 days, patient who commenced enteral feeding before 5 days and patient who commenced enteral feeding between 5 - 7 days were about 2.6 and 5 folds more likely to survive without neurological deficit.

Table 2 shows crude analysis of maternal factors that could have an influence on neonatal outcome following administration of magnesium Sulphate; however none of the maternal factors demonstrated significant correlation with survival outcomes.

Table 3 presents adjusted analysis of factors with p value, 0.05 in the crude analysis. On adjusted analysis none of the factors showed significant correlation as independent predictors of survival outcome in asphyxia treated with MgSO₄.

Table 4 shows the survival outcome of asphyxiated neonate treated with MgSO₄ compared across various grades of HIE. There is no significant association between each grade of HIE and survival outcome.

Figure 1 presents percentage with strong suckling reflex distributed after the last dose of MgSO₄ dose. The earlier the commencement of MgSO₄ therapy the better the percentage with strong suckling reflex at 5 days.

Figure 2 presents percentage with strong Palma grasp distributed by the time

of first MgSO₄ dose. The earlier the commencement of MgSO₄ therapy the better the percentage with strong palmar grasp reflex at 5 days.

Figure 3 shows a resolution of encephalopathy and normalization of muscle tone after administration of three doses of magnesium Sulphate.

Figure 4 shows general posture normalization as results of administration of 3 doses of intravenous magnesium Sulphate the severely asphyxiated with hypoxic-ischemic encephalopathy.

We also observed resolution of encephalopathy, normalization of muscle tone and posture. At 3 month in the follow up clinic, greater 50% were normal without neurodeficits.

Following severe perinatal asphyxia, hypoxic-ischemic injury of neonatal brain ensues and which said to occur in two phases. The primary phase respond to active resuscitative measures when carried promptly while the secondary phase lingers several hours to days and cause severe irreversible neuronal damages to the developing brain [7] . Glutamate acts on the N-methyle-D-aspartate (NMDA) receptor, a post-synaptic ion channel in the brain, and during asphyxia process, there excessive release and reduced uptake of glutamate in the newborn brain [17] . High concentrations of glutamate open channels, allowing excessive calcium influx into the neurons and induce irreversible neuronal. Magnesium Sulphate is a naturally occurring NMDA receptor antagonist that blocks neuronal influx of calcium within the ion channels. It has been found in several researches that when the extracellular concentration of magnesium is increased, then this block is restored thereby halting further brain damages [18] .

In this study, we administered to 52 severely asphyxiated neonates that were recruited consecutively after meeting the selection criteria magnesium Sulphate at 250 mg/kg/dose daily for the first 72 hours and monitored patients responses to the effects of the drug on the neurological resolution by way of restoration primitive reflexes and regain of consciousness. Approximately half (48%) of the mothers of asphyxiated babies had intrapartum pre/eclampsia, 26.9% had antepartum haemorrhages while more than 50% of the asphyxiated babies were born to obese mother. It was observed that magnesium Sulphate had neuroprotective effects on the study subjects of patients this was evidenced by early restoration of sucking reflexes. In this study majority of the subjects commenced initial feeding with nasogastric tubes (test feed), while full enteral feed by cup and spoon or direct breast feeding were commenced in less than 7 days in most of the patients, these were independent factors that also predicted the survival without neurodeficit as at the time of discharge from the hospital and follow up clinic at 6 weeks. This findings was similar to the reports by Bhat et al., [7] and Ichiba et al. [19] .

In this study we evaluated and monitored parameters inaddition early breastfeeding by way of early resumption of sucking reflex includes; normalization of palmar grasp, muscles and resolution of hypoxic ischemic encephalopathy, which was observed in more than 50% of the patients and was associated survival without neurologic abnormalities as at discharge and at 6 weeks follow in the clinic [20] . Just like in this study, magnesium Sulphate use in human neonates are few and many of the stated neuroprotective role of magnesium Sulphate has been largely done in animal models, with many evidence of favourable results in terms of amelioration of secondary neuronal injury [7] [21] . Unlike study by Bhat and colleagues [7] , this index study was randomized non-controlled interventional study, which included all asphyxiated neonates, however, during the study we did not encountered any adverse effects in the neonates; there was no bradycardia, no hypotension and even the few that had apnoea we attributed to severity of the hypoxic-ischemic brain damage before the interventions were instituted. Other workers have also reported similar findings where they found a rapid and good neurological improvement among moderately to severely asphyxiated neonates treated with 3 days daily doses of magnesium Sulphate infusion at 250 mg/kg [22] . Even though is an interventional trial, it shown a good effect on rapid resolution of hypoxia-ischaemia encephalopathy among magnesium Sulphate treated neonates HIE stage I-III.

We believe from our interventional trial, magnesium Sulphate has neuroprotective effect on severely asphyxiated neonates. If the treatment is administered early after the onset of asphyxia, it surely will halt and probably reverse the secondary neuronal damage due to hypoxic ischemic injury following severe perinatal asphyxia.

This study was non-controlled randomized magnesium Sulphate interventional trial; it will have been better if it were placeb-controlled trial but were unable to do that for ethical reasons. Also we stopped follow up at 3 months, preferably if the patients were followed up to 18 - 24 months post-magnesium study, so that the first two years of the subject growth and development would have more defined with respect to neuromotor deficits as consequences of severe perinatal asphyxia complication. Therefore we suggest further placebo-controlled trial be undertaken to make it robust and more detailed.

The authors are particularly appreciative of the Resident Doctors, Special care Baby Unit (SCBU) of the Department of Paediatrics for their support during the study.

The authors have no conflict of interest to declare.

The authors received small research grant from TETFUND for IBR. Ref. No. TETFUND/DESS/UNIMAID/MAIDUGURI/RP./VOL.VI. towards the study.

Pius, S., Bello, M., Ambe, J.P., Machoko, Y., Clement, A.Y., Genesis, R. and Kamas, M.I. (2019) Pilot Study: Magnesium Sulphate Administration and Early Resolution of Hypoxic Ischemic Encephalopathy in Severe Perinatal Asphyxia. Open Journal of Pediatrics, 9, 89-102. https://doi.org/10.4236/ojped.2019.91009