Magnesium therapy for newborn persistent pulmonary hypertension: a scoping review

Persistent pulmonary hypertension of the newborn, a life-threatening condition in which a baby’s circulatory system fails to make the transition from fetal to neonatal blood flow, has long frustrated neonatologists with limited pharmacological options. Now, a new scoping review published in the Journal of Perinatology has systematically mapped the existing evidence on one of the oldest and most debated candidates in the treatment arsenal: magnesium sulfate. The review, led by Y. Dadon and colleagues including F.B. Mimouni and I. Arad, brings together decades of scattered clinical experience with magnesium therapy in newborns with PPHN, and its conclusions carry significant weight for a field where the gold-standard therapy remains inaccessible to much of the world’s neonatal population.

PPHN arises when the pulmonary vascular resistance, which is normally high in the fetus, fails to drop after birth. In healthy newborns, the first breaths inflate the lungs, oxygen levels rise, and the pulmonary arteries dilate dramatically, allowing blood to flow through the lungs for oxygenation instead of bypassing them through the ductus arteriosus and foramen ovale as it did in utero. In babies with PPHN, this transition stalls. The pulmonary vessels remain constricted, blood continues to shunt away from the lungs, and the infant develops severe hypoxemia that standard ventilation often cannot correct. The condition affects an estimated one to two per thousand live births and, despite advances in care, mortality remains substantial, with survivors facing elevated risks of neurodevelopmental impairment.

The therapeutic landscape for PPHN is dominated by inhaled nitric oxide, a selective pulmonary vasodilator that has demonstrably reduced the need for extracorporeal membrane oxygenation, or ECMO, in term and near-term infants. But iNO is expensive, requires sophisticated delivery equipment and round-the-clock monitoring, and is simply unavailable in many neonatal intensive care units, particularly in low- and middle-income countries where the burden of birth asphyxia-related PPHN is highest. This gap has sustained interest in cheaper, easier-to-administer alternatives, and magnesium sulfate, long used in obstetrics for eclampsia and in adults for pulmonary hypertension and arrhythmias, has been the most prominent of these candidates.

Magnesium’s proposed mechanism in PPHN is biologically plausible and rests on its role as a natural calcium channel blocker. Pulmonary vasoconstriction in PPHN is driven in large part by elevated cytosolic calcium in vascular smooth muscle cells. By competing with calcium at membrane channels and reducing calcium influx, magnesium ions promote smooth muscle relaxation and thereby pulmonary vasodilation. Magnesium also modulates endothelial function, influences nitric oxide synthesis, and dampens the release of inflammatory mediators, all of which may contribute to lowering pulmonary vascular tone. Unlike inhaled nitric oxide, which acts locally on the pulmonary vasculature and is rapidly inactivated by hemoglobin, intravenous magnesium exerts systemic effects, raising the specter of systemic hypotension, a side effect that has shaped much of the clinical debate.

It is precisely this duality, cheap and accessible on one hand, systemically vasodilating and potentially hazardous on the other, that makes magnesium therapy in PPHN such a contested topic. Individual trials and observational studies over the past several decades have reported conflicting results. Some investigators described improvements in oxygenation indices, such as the oxygenation index and alveolar-arterial oxygen gradient, following magnesium infusion, while others found no meaningful benefit and documented troubling rates of hypotension and hypocalcemia. The heterogeneity of these studies, in patient populations, in dosing regimens, in co-interventions, and in outcome measures, has made it nearly impossible to draw firm conclusions from any single report. A scoping review is designed exactly for this kind of fragmented evidence base: rather than pooling data statistically as a meta-analysis would, it systematically charts the breadth of available research, cataloguing what has been studied, how, and with what results, while explicitly identifying the gaps that future work must fill.

The new review by Dadon and colleagues does precisely that, assembling the published literature on magnesium sulfate for PPHN and organizing it around four axes: efficacy, safety, mechanisms of action, and knowledge gaps. In doing so, it functions less as a verdict and more as a map, showing clinicians and researchers where the evidence is thick and where it is perilously thin. The authors’ choice of a scoping review methodology signals an important acknowledgment: the literature on magnesium in PPHN is too heterogeneous, and in places too methodologically weak, for the kind of definitive meta-analysis that would justify or condemn the therapy outright.

The safety dimension deserves particular attention, because magnesium is not a benign drug in newborns. Excessive magnesium levels are associated with vasodilation that can precipitate systemic hypotension, the very complication that can worsen coronary and cerebral perfusion in a critically ill neonate. Magnesium also crosses the placenta, and infants born to mothers treated with magnesium sulfate for preeclampsia or tocolysis can exhibit neonatal hypermagnesemia, with clinical signs ranging from hypotonia and respiratory depression to feeding difficulties. In the PPHN context, where the therapeutic window between effective pulmonary vasodilation and dangerous systemic effects is narrow and poorly defined, monitoring of serum magnesium levels becomes essential, yet the review reveals that monitoring practices across studies have been inconsistent at best.

Equally important is what the review highlights as unresolved: optimal dosing. The studies examined employed a variety of loading doses and infusion rates, often borrowed from adult or obstetric practice rather than derived from neonatal pharmacokinetic studies. Neonatal magnesium clearance differs from that of older patients, influenced by gestational age, renal function, and concurrent illness, and no consensus exists on what serum magnesium concentration represents the therapeutic sweet spot for pulmonary vasodilation. This pharmacokinetic uncertainty compounds the clinical uncertainty, and it represents one of the most clearly articulated knowledge gaps identified by the authors.

The broader significance of the review lies in the global health dimension of PPHN care. Inhaled nitric oxide and ECMO are concentrated in high-resource tertiary centers, while a large share of the world’s PPHN births occur in settings where neither is available. If magnesium sulfate could be shown to be safe and effective with a properly defined dosing protocol, it would offer an affordable, widely implementable option for units that currently have little to offer beyond mechanical ventilation and supportive care. Conversely, if rigorous trials were to show that the risks of systemic hypotension outweigh any oxygenation benefit, the review would serve the equally valuable function of closing the door on a therapy that persists largely on tradition and anecdote. Either way, the field moves forward only through the kind of systematic stocktaking this review provides.

The authors also underscore the need for standardized outcome reporting in future studies of PPHN therapies. Historically, trials in this population have measured everything from oxygenation indices and echocardiographic estimates of pulmonary pressure to mortality, ECMO utilization, and long-term neurodevelopmental outcomes, often in incomparable ways. Without harmonized endpoints and adequately powered, randomized, controlled designs, the question of magnesium’s role in PPHN will remain open indefinitely. The scoping review effectively lays the groundwork for such trials by identifying which questions matter most and which methodological pitfalls have undermined earlier efforts.

For neonatologists at the bedside, the practical takeaway is one of cautious agnosticism. Magnesium sulfate should not be regarded as a proven therapy for PPHN, but neither should its use be dismissed outright in centers with no access to inhaled nitric oxide, where the alternative to a modestly evidenced vasodilator may be nothing at all. What the review makes clear is that any such use should be accompanied by careful serum magnesium monitoring, vigilant attention to blood pressure, and a candid acknowledgment that the evidence base remains incomplete. The days of extrapolating from adult and obstetric practice without neonatal-specific data should, the authors suggest, be numbered.

As the field awaits the definitive randomized trials that the review implicitly calls for, the work of Dadon, Mimouni, Arad, and their colleagues stands as a reminder of an often-overlooked truth in clinical medicine: that mapping the limits of knowledge is itself a scientific contribution. In a condition as unforgiving as persistent pulmonary hypertension of the newborn, where minutes of hypoxemia can shape a child’s entire neurodevelopmental trajectory, knowing precisely what we do not know about a widely available, inexpensive drug is the essential first step toward finding out whether it belongs in the neonatal intensive care unit, and under what conditions.