A Systematic Review of Magnesium Sulfate for Perinatal Neuroprotection: What Have We Learnt From the Past Decade?

Abstract

There is an important unmet need to improve long term outcomes of encephalopathy for preterm and term infants. Meta-analyses of large controlled trials suggest that maternal treatment with magnesium sulfate (MgSO₄) is associated with a reduced risk of cerebral palsy and gross motor dysfunction after premature birth. However, to date, follow up to school age has found an apparent lack of long-term clinical benefit. Because of this inconsistency, it remains controversial whether MgSO₄ offers sustained neuroprotection. We systematically reviewed preclinical and clinical studies reported from January 1 2010, to January 31 2020 to evaluate the most recent advances and knowledge gaps relating to the efficacy of MgSO₄ for the treatment of perinatal brain injury. The outcomes of MgSO₄ in preterm and term-equivalent animal models of perinatal encephalopathy were highly inconsistent between studies. None of the perinatal rodent studies that suggested benefit directly controlled body or brain temperature. The majority of the studies did not control for sex, study long term histological and functional outcomes or use pragmatic treatment regimens and many did not report controlling for potential study bias. Finally, most of the recent preterm or term human studies that tested the potential of MgSO₄ for perinatal neuroprotection were relatively underpowered, but nevertheless, suggest that any improvements in neurodevelopment were at best modest or absent. On balance, these data suggest that further rigorous testing in translational preclinical models of perinatal encephalopathy is essential to ensure safety and best regimens for optimal preterm neuroprotection, and before further clinical trials of MgSO₄ for perinatal encephalopathy at term are undertaken.

Keywords: brain injury; cerebral palsy; hypoxic-ischemic encephalopathy; magnesium sulfate; neuroprotection; perinatal encephalopathy.

Figure 1

Flow chart illustrating the number of papers identified through database searching and other relevant sources, the number of full-text articles screened, assessed, and excluded, and the final number of original papers surveyed. Preclinical publications that performed ontogeny assessment of outcomes, used more than one paradigm of encephalopathy or multiple treatment timings were further sub-divided if outcomes differed according to age at assessment, experimental paradigm or treatment timing. After subdividing these publications, there was a revised total of 22 preclinical studies. For the purpose of reporting on the preclinical literature we have summarized the data based on the individual studies (n = 22).