Antenatal Magnesium Sulfate: As a Neuroprotective Agent in Preterm Neonates

Intraventricular Hemorrhage (IVH) remains a catastrophic neurological complication with considerable mortality and neurodevelopmental disability in preterm neonates. Given that preterm birth is a major cause, many strategies have been put forth for its prevention. The newest on the present-day list is Magnesium Sulphate.

The 2023 WHO Born Too Soon Report highlights that preterm birth (delivery at viability but before 37 weeks of gestation) remains the greatest contributor to neonatal and infant mortality worldwide and is one of the greatest contributors to lost human capital [1]. Babies born prematurely often face a range of complications due to their underdeveloped organs and systems. Common issues include respiratory distress from immature lungs, which can lead to conditions like respiratory distress syndrome and bronchopulmonary dysplasia. Cardiovascular concerns such as patent ductus arteriosus and hypotension are also prevalent. Neurological complications, including intraventricular hemorrhage and periventricular leukomalacia, can affect brain development and function. Additionally, preterm infants may suffer from gastrointestinal problems like necrotizing enterocolitis and feeding difficulties, as well as an increased susceptibility to infections due to an immature immune system. Metabolic issues like hypoglycemia and electrolyte imbalances are common, along with challenges in maintaining body temperature. 

Intraventricular hemorrhage, being an area of concern, is one of the most common types of brain injury in preterm infants [2]. IVH is primarily caused by destabilizing changes in cerebral blood flow inflicting to the microvasculature of the germinal matrix [3]. Embryologically, the GM is the source of both neurons and glial cells, and it is active mainly between 8 and 28 weeks of gestation. The GM initially produces neurons and subsequently glial cells, which migrate to populate the cerebral cortex. Involution of the GM toward the caudothalamic groove begins late in the second trimester and is nearly completed by 32 weeks of gestation.

Anatomically, the GM is a highly vascularized region of the developing brain located underneath the lateral ventricles. The GM has been referred to as an “immature vascular rete” containing primitive vessels that cannot be classified as arterioles, venules, or capillaries. The GM microvasculature is fragile and this fragility is derived from the histological feature of a single layer of surrounding endothelial cells and a scarcity of pericytes. Furthermore, the GM microvasculature lacks the basement membrane deposition, tight junctions and glial end foot investiture, all of which physiologically constitute the blood-brain barrier. These anatomical features make it more prone to injury and bleeding. Infants most at risk are those born before 33 weeks of gestational age, as after this time, the germinal matrix involutes [4]. On the other hand, in preterm infants with immature cardiopulmonary systems, vital signs are considerably unstable during the first few days of life and complications such as respiratory distress syndrome can also occur. Therefore hypotension, hypoxia and hypercapnia are common. As cerebral autoregulation is also immature, CBF fluctuation can cause repeated ischemia-reperfusion events and a sudden increase in CBF can lead to excessive strain on fragile vessels in the GM, resulting in hemorrhage [5].

Studies have been conducted with many pharmacologic agents predicting that these agents could prevent IVH. However, the only pharmacologic agent that has been found to be efficient so far is antenatal steroids 6. Recently, Magnesium sulphate, which is being used as a tocolytic and a prophylactic agent against convulsions in pre-eclamptic women, is gaining fame in the field of neuroprotection. MgSO4 has been proposed to act as a neuroprotectant by reducing inflammatory cytokines or free radicals produced during hypoxic-ischemic reperfusion, preventing excitotoxic calcium-induced injury, membrane stabilization by preventing the membrane depolarization, inhibiting glutamate receptors involved in injury to preoligodendrocytes, stabilizing fluctuations in blood pressure that occur in neonates and an increase in cerebral blood flow [7]. The RCOG [8] and NG25 [9] recommended offering magnesium sulfate to women who are in established labour or having a planned preterm birth within 24 hours before 30 weeks of gestation (as benefit is greatest). FIGO [10] good practice recommendations on magnesium sulfate administration for preterm fetal neuroprotection recommnends its use in pregnancies below 32-34 weeks of gestation (2021). 

Animal and human observational studies have suggested that MgSO4 is neuroprotective for the immature brain. Although the exact processes underlying this neuroprotective effect are unknown, research have pointed to a number of potential explanations. According to Nowak et al. (1984) and Kang et al. (2011), magnesium can lessen excitotoxicity by inhibiting the N-methyl-D-aspartic acid (NMDA) receptor and reducing extracellular glutamate. Furthermore, by modulating pro-inflammatory cytokines and oxidative stress, magnesium may exhibit anti-inflammatory effects (Mazur et al., 2007; Burd et al., 2010; Rayssiguier et al., 2010) [11].  Magnesium is an abundant cation in the body that plays an important role in several intracellular mechanisms [12] like glycolysis, oxidative phosphorylation, protein synthesis and maintenance of cell membrane integrity. The neuroprotective effects of MgSO4 for the fetus are due to various proposed mechanisms such as effects on cellular metabolism, decreased cell death by inhibition of calcium influx-mediated neuronal apoptosis, decreased cell injury by reduction in proinflammatory agents [13]. There is some evidence that magnesium reduces the production of pro-inflammatory cytokines and free radicles following hypoxic ischemic reperfusion and also prevents calcium- induced injury [14]. It may reduce injury by preventing excess glutamate from overactivating the NMDA-dependent calcium channel due to occupation of the Mg2+ sites within the cation channels. As a result, it inactivates the NMDA receptor and preclude Ca ions overload. Recently, magnesium salts have shown to block the voltage-sensitive K+ channels, calcium-sensitive K+ channels, ATP-sensitive K+ channels and Ca2+ channels in vascular smooth muscle and vascular endothelial cells in the placental human vessels. On the other hand, magnesium determines a tissue protection against activity of free radicals and its low level enhances lipids peroxidation [12].

Multiple studies have been conducted for exploring the neuroprotective effect of antennal MgSo4 for premature infants. Nidhi et al [15] (2021) conducted a study which suggested that in control group ,4% had IVH and 6% had periventricular leukomalacia compared to nil cases of IVH in MgSO4 group (p=0.14). Bansal et al [16] (2021) conducted a study in which all surviving infants (n-93) underwent a cranial ultrasound within the first 14 days of life. On neurosonogram, 2 infants showed (periventricular leukomalacia) PVL, one each in MgSO4 and non-MgSO4 group and 12 infants had IVH (Intraventricular hemorrhage). IVH was more often seen in non-MgSO4 group (8/12) as compared to MgSO4 group (4/12). All of these studies and inquiries contribute to the growing body of proof regarding the therapeutic value of this miraculous medication. Particularly infants born at an earlier gestational age are at higher risk for cerebral palsy. The incidence of CP is much higher in children born extremely prematurely, occurring in approximately 20% of children born at ≤26 weeks gestational age but in only 4% of children born at 32 weeks’ gestational age [17]. Three trials (Rouse et al (2008), Marret et al (2006), Crowther et al (2003)) consisting of 4387 infants was conducted and they showed that moderate or severe cerebral palsy was significantly reduced in the group who received MgSO4. If these results are extrapolated to a neonate's long-term neurodevelopmental outcomes, it will substantially enhance his or her prognosis. 

Cochrane review included six RCTs (5917 women and their 6759 fetuses alive at randomisation) which compared magnesium sulphate with placebo in women at risk of preterm birth at less than 34 weeks' gestation; however, treatment regimens and inclusion/exclusion criteria varied.  Magnesium sulphate probably reduced severe intraventricular haemorrhage (grade 3 or 4)(RR 0.76, 95% CI 0.60 to 0.98; 5 RCTs, 5885 infants; NNTB 92, 95% CI 55 to 1102; moderate-certainty evidence) and may have resulted in little to no difference in chronic lung disease/bronchopulmonary dysplasia (average RR 0.92, 95% CI 0.77 to 1.10; 5 RCTs, 6689 infants; low-certainty evidence) and so indicates that magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus, compared with placebo, reduces cerebral palsy, and death or cerebral palsy, in children up to two years' corrected age, and probably reduces severe intraventricular haemorrhage for infants [18].

Also antenatal magnesium sulfate (MgSO4) could possibly alleviate other life threatening complications. Various methods are known to evaluate their overall health and determine if immediate medical intervention is needed. The APGAR score is a quick and simple assessment performed on a newborn at one and five minutes after birth. A higher score indicates better overall health, while a lower score may suggest that the baby needs medical attention. Therefore, it helps healthcare providers quickly assess the newborn's condition and make decisions about the need for immediate care or intervention. Preterm infants often require respiratory support due to their immature lung development and associated breathing difficulties. Born before their lungs are fully developed, these infants frequently lack adequate surfactant, a substance essential for keeping the tiny air sacs in the lungs open and functioning properly. As a result, they are at high risk for respiratory distress syndrome (RDS), characterized by severe breathing difficulties. Head growth in early neonatal life is indeed a critical aspect of development, as it reflects brain growth and overall health. At birth, the human brain is about 25% of its adult weight, and it undergoes rapid development and growth during the first few years of life. By the age of around 10 years, the brain reaches approximately 90% of its adult size [19]. Pediatricians closely track head circumference to ensure that it is progressing normally, as deviations from expected growth patterns can indicate potential developmental or health issues. Poor head growth in preterm infants can be an early sign of neurodevelopmental issues and may correlate with later cognitive and developmental challenges.

Preterm birth interrupts the pattern of normal brain development in the in-utero environment, and is associated with smaller brain volumes and altered white matter microstructure during early childhood and adolescence. In a study conducted by Brumbaugh JE 2016, children born late preterm (34 to 36 weeks) had smaller volumes of the total tissue (i.e., cerebral cortex and cerebral white matter) and thalamus compared with their term-born peers at 6 to 13 years [20]. The complications of preterm birth arise from immature organ systems that are not yet prepared to support life in the extrauterine environment. The risk of acute neonatal illness decreases with gestational age, reflecting the fragility and immaturity of the brain, lungs, immune system, kidneys, skin, eyes, and gastrointestinal system. In general, more immature preterm infants require more life support.  Numerous of these issues have long-term effects on the development, growth, and health of prematurely born children. While a few treatments for neonates have been shown to be safe and beneficial in some randomized, controlled studies, most common treatments and interventions have not received enough research attention. Antenatal MgSO4 has shown promising results in previous studies. Further research work needs to be done to proove its promising nature.

Magnesium is a substance which has been used for decades in the field of obstetrics as a prophylaxis for eclamptic seizures and tocolysis. Likewise, benefits of magnesium have been extrapolated to the area of premature newborns' neuroprotective deficit. Its neuroprotective potential have been a focus of numerous published scientific studies in the last few decades.