Researchers suggest there is little benefit in using intravenous magnesium sulphate preterm birth – at 30 to 34 weeks’ gestation – after their randomised trial showed it failed to improve survival and incidence of cerebral palsy (CP) among infants up to two years’ post-delivery.
Dr Caroline Crowther and colleagues from the University of Auckland, New Zealand, said that in their MAGENTA trial, the primary outcome analysis that included 1 365 children found death or cerebral palsy assessed by a paediatrician at two years’ corrected age occurred in 3.3% of those in the magnesium group and 2.7% of those in the placebo group (adjusted relative risk [RR] 1.19, 95% CI 0.65-2.18, P=0.57).
There were 12 deaths in the magnesium group versus seven deaths in the placebo group by two years of age (aRR 1.50, 95% CI 0.58-3.86, P=0.40), while 1.6% versus 1.7%, respectively, had cerebral palsy (aRR 0.98, 95% CI 0.43-2.23, P=0.96), they wrote in JAMA Network.
Crowther told MedPage Today that “cerebral palsy remains the most frequent cause of severe motor disability in childhood and preterm birth is a principal risk factor”.
“As there is no cure for cerebral palsy, primary prevention is critical.
“Although clinical practice guidelines worldwide now recommend prenatal magnesium sulphate before preterm birth for foetal neuroprotection, there is a lack of consensus, due to limited data, regarding the optimal gestational ages for its use,” she added.
The study authors said their trial’s findings contrast with others that have identified a benefit of intravenous magnesium for children born at earlier gestational ages.
The reason for the lack of effect in the age range of 30 to 34 weeks’ gestation is unclear.
“The risk differences for the combined outcome of death or cerebral palsy, and its components of death and cerebral palsy in the current trial, are consistent with the treatment effect and CIs reported in (a prior) meta-analysis among the age subgroups of 30 to 31 weeks’ gestation and 32 weeks’ gestation or longer,” they wrote.
“It is possible that the mechanism of brain injury – by which extremely preterm birth leads to cerebral palsy – may be different from mechanisms relevant at later gestational ages.”
In an accompanying editorial in JAMA Network, Dr Judette Marie Louis and Dr Tara Marie Randis, both of the University of South Florida, noted that concerns about other adverse outcomes with the administration of prenatal magnesium have been reported over the past decade.
“Most of these have focused on gastrointestinal complications in infants born before 25 weeks’ gestation, including an increased risk of meconium-related ileus, spontaneous intestinal perforation, and necrotising enterocolitis,” they wrote.
“A 2019 systematic review and meta-analysis designed to examine the association between prenatal magnesium sulphate administration, perinatal death, and other unintended adverse neonatal outcomes, revealed no clear link, providing reassurance regarding the safety of this practice.”
“Nevertheless, given a lack of benefit in this current cohort of infants, care must be taken to avoid therapeutic creep and the potential for unintended harm,” they concluded. “The time has come to limit intrapartum magnesium for neurological protection to patients who are at risk to give birth before 30 weeks’ gestation.”
Of note in the current study, newborns in the magnesium group were less likely to have respiratory distress syndrome compared with the placebo group (34% vs 41%, respectively; aRR 0.85, 95% CI 0.76-0.95), as well as chronic lung disease (5.6% vs 8.2%; aRR 0.69, 95% CI 0.48-0.99) during hospitalisation at birth.
However, children exposed to magnesium were more likely to have overall behavioural scores within the clinical problem range: 10% in the magnesium group compared with 6% in the placebo group (aRR 1.66, 95% CI 1.03-2.68, P=0.04).
“Significant findings for some of the secondary outcomes were unexpected, particularly the neonatal benefits of less respiratory distress syndrome and chronic lung disease in babies exposed to magnesium sulphate,” Crowther said.
“The suggestion of more behavioural problems in children whose mothers were given magnesium sulphate was also unexpected, although later follow-up to early school age in previous trials has not shown such differences between children exposed or not.”
In the MAGENTA study, 56% of the mothers in the magnesium group had a Caesarean delivery versus 61% in the placebo group (aRR 0.91, 95% CI 0.84-0.99), but more women in the magnesium group had a major postpartum haemorrhage (3.4% vs 1.7%, respectively; aRR 1.98, 95% CI 1.01-3.91).
The research was conducted at 24 Australian and New Zealand hospitals from January 2012 to April 2018, among 1 433 pregnant women. Mean age was 30.6. Of the 1 679 infants, 81% were included in the primary outcome analysis: 691 were randomised to 4-g intravenous magnesium sulphate and 674 were given placebo.
The primary outcome was death (stillbirth, death of a live-born infant before hospital discharge, or death after hospital discharge) before two years’ corrected age or cerebral palsy (loss of motor function and abnormalities of muscle tone and power assessed by a paediatrician) at two years' corrected age.
Overall, there were no serious cardiovascular or respiratory adverse outcomes from the study infusion among mothers. Adverse events such as nausea, vomiting, flushing, arm discomfort, dry mouth, dizziness, and blurred vision occurred in 77% of those in the magnesium group compared with 20% of the placebo group.
Crowther and colleagues noted that because event rates for death and cerebral palsy were lower than predicted, the sample size “lacked power to detect small but potentially important differences in the risk of death or cerebral palsy”.
In addition, the findings are most likely only generalisable to similar healthcare settings, which in this case were publicly funded and well-coordinated facilities in two high-income countries.
“Further assessment on the efficacy and safety of magnesium for neuroprotection in lower-resource settings is warranted,” they wrote.
Study details
Prenatal Intravenous Magnesium at 30-34 Weeks’ Gestation and Neurodevelopmental Outcomes in Offspring: The MAGENTA Randomised Clinical Trial
Caroline A. Crowther, Pat Ashwood, Philippa Middleton, et al.
Published in JAMA Network on 15 August 2023
Key Points
Question Does intravenous magnesium sulphate for pregnant individuals at risk of delivery between 30 and 34 weeks’ gestation reduce the risk of death or cerebral palsy in their children?
Findings This randomised clinical trial including 1433 pregnant individuals at risk of preterm delivery and their 1679 infants found no significant difference in death or cerebral palsy at 2 years’ corrected age among children exposed to magnesium sulphate compared with placebo.
Meaning Magnesium sulphate prior to preterm birth between 30 and 34 weeks’ gestation did not increase the chance of child survival without cerebral palsy, although this study had limited power to detect an effect.
Abstract
Importance
Intravenous magnesium sulphate administered to pregnant individuals before birth at less than 30 weeks’ gestation reduces the risk of death and cerebral palsy in their children. The effects at later gestational ages are unclear.
Objective
To determine whether administration of magnesium sulphate at 30 to 34 weeks’ gestation reduces death or cerebral palsy at 2 years.
Design, Setting, and Participants
This randomised clinical trial enrolled pregnant individuals expected to deliver at 30 to 34 weeks’ gestation and was conducted at 24 Australian and New Zealand hospitals between January 2012 and April 2018.
Intervention
Intravenous magnesium sulphate (4 g) was compared with placebo.
Main Outcomes and Measures
The primary outcome was death (stillbirth, death of a live-born infant before hospital discharge, or death after hospital discharge before 2 years’ corrected age) or cerebral palsy (loss of motor function and abnormalities of muscle tone and power assessed by a paediatrician) at 2 years’ corrected age. There were 36 secondary outcomes that assessed the health of the pregnant individual, infant, and child.
Results
Of the 1433 pregnant individuals enrolled (mean age, 30.6 [SD, 6.6] years; 46 [3.2%] self-identified as Aboriginal or Torres Strait Islander, 237 [16.5%] as Asian, 82 [5.7%] as Māori, 61 [4.3%] as Pacific, and 966 [67.4%] as white) and their 1679 infants, 1365 (81%) offspring (691 in the magnesium group and 674 in the placebo group) were included in the primary outcome analysis. Death or cerebral palsy at 2 years’ corrected age was not significantly different between the magnesium and placebo groups (3.3% [23 of 691 children] vs 2.7% [18 of 674 children], respectively; risk difference, 0.61% [95% CI, −1.27% to 2.50%]; adjusted relative risk [RR], 1.19 [95% CI, 0.65 to 2.18]). Components of the primary outcome did not differ between groups. Neonates in the magnesium group were less likely to have respiratory distress syndrome vs the placebo group (34% [294 of 858] vs 41% [334 of 821], respectively; adjusted RR, 0.85 [95% CI, 0.76 to 0.95]) and chronic lung disease (5.6% [48 of 858] vs 8.2% [67 of 821]; adjusted RR, 0.69 [95% CI, 0.48 to 0.99]) during the birth hospitalisation. No serious adverse events occurred; however, adverse events were more likely in pregnant individuals who received magnesium vs placebo (77% [531 of 690] vs 20% [136 of 667], respectively; adjusted RR, 3.76 [95% CI, 3.22 to 4.39]). Fewer pregnant individuals in the magnesium group had a Caesarean delivery vs the placebo group (56% [406 of 729] vs 61% [427 of 704], respectively; adjusted RR, 0.91 [95% CI, 0.84 to 0.99]), although more in the magnesium group had a major postpartum haemorrhage (3.4% [25 of 729] vs 1.7% [12 of 704] in the placebo group; adjusted RR, 1.98 [95% CI, 1.01 to 3.91]).
Conclusions and Relevance
Administration of intravenous magnesium sulphate prior to preterm birth at 30 to 34 weeks’ gestation did not improve child survival free of cerebral palsy at 2 years, although the study had limited power to detect small between-group differences.
MedPage Today article – Later Prenatal Magnesium No Help for Kids' Cerebral Palsy Risk (Open access)
See more from MedicalBrief archives:
Magnesium sulphate shown to reduce cerebral palsy risk in preterm babies – UK study
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Earlier survival of prem babies raises questions