Prenatal Magnesium Sulfate and Functional Connectivity in Offspring at Term-Equivalent Age.

Importance: Understanding the effect of antenatal magnesium sulfate (MgSO4) treatment on functional connectivity will help elucidate the mechanism by which it reduces the risk of cerebral palsy and death. Objective: To determine whether MgSO4 administered to women at risk of imminent preterm birth at a gestational age between 30 and 34 weeks is associated with increased functional connectivity and measures of functional segregation and integration in infants at term-equivalent age, possibly reflecting a protective mechanism of MgSO4. Design, Setting, and Participants: This cohort study was nested within a randomized placebo-controlled trial performed across 24 tertiary maternity hospitals. Participants included infants born to women at risk of imminent preterm birth at a gestational age between 30 and 34 weeks who participated in the MAGENTA (Magnesium Sulphate at 30 to 34 Weeks' Gestational Age) trial and underwent magnetic resonance imaging (MRI) at term-equivalent age. Ineligibility criteria included illness precluding MRI, congenital or genetic disorders likely to affect brain structure, and living more than 1 hour from the MRI center. One hundred and fourteen of 159 eligible infants were excluded due to incomplete or motion-corrupted MRI. Recruitment occurred between October 22, 2014, and October 25, 2017. Participants were followed up to 2 years of age. Analysis was performed from February 1, 2021, to February 27, 2024. Observers were blind to patient groupings during data collection and processing. Exposures: Women received 4 g of MgSO4 or isotonic sodium chloride solution given intravenously over 30 minutes. Main Outcomes and Measures: Prior to data collection, it was hypothesized that infants who were exposed to MgSO4 would show enhanced functional connectivity compared with infants who were not exposed. Results: A total of 45 infants were included in the analysis: 24 receiving MgSO4 treatment and 21 receiving placebo; 23 (51.1%) were female and 22 (48.9%) were male; and the median gestational age at scan was 40.0 (IQR, 39.1-41.1) weeks. Treatment with MgSO4 was associated with greater voxelwise functional connectivity in the temporal and occipital lobes and deep gray matter structures and with significantly greater clustering coefficients (Hedge g, 0.47 [95% CI, -0.13 to 1.07]), transitivity (Hedge g, 0.51 [95% CI, -0.10 to 1.11]), local efficiency (Hedge g, 0.40 [95% CI, -0.20 to 0.99]), and global efficiency (Hedge g, 0.31 [95% CI, -0.29 to 0.90]), representing enhanced functional segregation and integration. Conclusions and Relevance: In this cohort study, infants exposed to MgSO4 had greater voxelwise functional connectivity and functional segregation, consistent with increased brain maturation. Enhanced functional connectivity is a possible mechanism by which MgSO4 protects against cerebral palsy and death.

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus.

BACKGROUND: Magnesium sulphate is a common therapy in perinatal care. Its benefits when given to women at risk of preterm birth for fetal neuroprotection (prevention of cerebral palsy for children) were shown in a 2009 Cochrane review. Internationally, use of magnesium sulphate for preterm cerebral palsy prevention is now recommended practice. As new randomised controlled trials (RCTs) and longer-term follow-up of prior RCTs have since been conducted, this review updates the previously published version. OBJECTIVES: To assess the effectiveness and safety of magnesium sulphate as a fetal neuroprotective agent when given to women considered to be at risk of preterm birth. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 17 March 2023, as well as reference lists of retrieved studies. SELECTION CRITERIA: We included RCTs and cluster-RCTs of women at risk of preterm birth that assessed prenatal magnesium sulphate for fetal neuroprotection compared with placebo or no treatment. All methods of administration (intravenous, intramuscular, and oral) were eligible. We did not include studies where magnesium sulphate was used with the primary aim of preterm labour tocolysis, or the prevention and/or treatment of eclampsia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed RCTs for inclusion, extracted data, and assessed risk of bias and trustworthiness. Dichotomous data were presented as summary risk ratios (RR) with 95% confidence intervals (CI), and continuous data were presented as mean differences with 95% CI. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included six RCTs (5917 women and their 6759 fetuses alive at randomisation). All RCTs were conducted in high-income countries. The RCTs 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. Though the RCTs were at an overall low risk of bias, the certainty of evidence ranged from high to very low, due to concerns regarding study limitations, imprecision, and inconsistency. Primary outcomes for infants/children: Up to two years' corrected age, magnesium sulphate compared with placebo reduced cerebral palsy (RR 0.71, 95% CI 0.57 to 0.89; 6 RCTs, 6107 children; number needed to treat for additional beneficial outcome (NNTB) 60, 95% CI 41 to 158) and death or cerebral palsy (RR 0.87, 95% CI 0.77 to 0.98; 6 RCTs, 6481 children; NNTB 56, 95% CI 32 to 363) (both high-certainty evidence). Magnesium sulphate probably resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.96, 95% CI 0.82 to 1.13; 6 RCTs, 6759 children); major neurodevelopmental disability (RR 1.09, 95% CI 0.83 to 1.44; 1 RCT, 987 children); or death or major neurodevelopmental disability (RR 0.95, 95% CI 0.85 to 1.07; 3 RCTs, 4279 children) (all moderate-certainty evidence). At early school age, magnesium sulphate may have resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.82, 95% CI 0.66 to 1.02; 2 RCTs, 1758 children); cerebral palsy (RR 0.99, 95% CI 0.69 to 1.41; 2 RCTs, 1038 children); death or cerebral palsy (RR 0.90, 95% CI 0.67 to 1.20; 1 RCT, 503 children); and death or major neurodevelopmental disability (RR 0.81, 95% CI 0.59 to 1.12; 1 RCT, 503 children) (all low-certainty evidence). Magnesium sulphate may also have resulted in little to no difference in major neurodevelopmental disability, but the evidence is very uncertain (average RR 0.92, 95% CI 0.53 to 1.62; 2 RCTs, 940 children; very low-certainty evidence). Secondary outcomes for infants/children: 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). Primary outcomes for women: Magnesium sulphate may have resulted in little or no difference in severe maternal outcomes potentially related to treatment (death, cardiac arrest, respiratory arrest) (RR 0.32, 95% CI 0.01 to 7.92; 4 RCTs, 5300 women; low-certainty evidence). However, magnesium sulphate probably increased maternal adverse effects severe enough to stop treatment (average RR 3.21, 95% CI 1.88 to 5.48; 3 RCTs, 4736 women; moderate-certainty evidence). Secondary outcomes for women: Magnesium sulphate probably resulted in little to no difference in caesarean section (RR 0.96, 95% CI 0.91 to 1.02; 5 RCTs, 5861 women) and postpartum haemorrhage (RR 0.94, 95% CI 0.80 to 1.09; 2 RCTs, 2495 women) (both moderate-certainty evidence). Breastfeeding at hospital discharge and women's views of treatment were not reported. AUTHORS' CONCLUSIONS: The currently available evidence 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. Magnesium sulphate may result in little to no difference in outcomes in children at school age. While magnesium sulphate may result in little to no difference in severe maternal outcomes (death, cardiac arrest, respiratory arrest), it probably increases maternal adverse effects severe enough to stop treatment. Further research is needed on the longer-term benefits and harms for children, into adolescence and adulthood. Additional studies to determine variation in effects by characteristics of women treated and magnesium sulphate regimens used, along with the generalisability of findings to low- and middle-income countries, should be considered.

Saudi Cerebral Palsy Register (SCPR): Protocol on the Methods and Technical Details.

This protocol presents a comprehensive proposal for the establishment of the Saudi Cerebral Palsy Register (SCPR), a crucial project for investigating and addressing the prevalence, etiology, and management of cerebral palsy (CP) in Saudi Arabia. The SCPR will not only provide a robust database for ongoing research and analysis but will also serve as a platform for investigating the causes of CP, implementing preventative strategies, and improving the quality of care and outcomes for people with CP and their families in Saudi Arabia. Detailed case definitions, inclusion/exclusion criteria, and data collection protocols are discussed to ensure the integrity and comparability of the data. The plan also outlines strategic funding, institutional and government endorsement, sustainability considerations, potential challenges and proposed solutions, and expected outcomes and impact. These include creating research and educational opportunities, fostering regional and international collaborations, and significantly contributing to CP prevention strategies. Overcoming anticipated obstacles, such as stigma, institutional policies, and collaborations, and securing both necessary funding and endorsements are highlighted as critical for the success of the SCPR. The project is not only aligned with promote prevention of health risks, a target of Vision 2030 in Saudi Arabia, but is also expected to have a substantial impact on the health and quality of life of people with CP and their families in Saudi Arabia, serving as inspiration for similar efforts worldwide.

Quality improvement interventions to increase the uptake of magnesium sulphate in preterm deliveries for the prevention of cerebral palsy (PReCePT study): a cluster randomised controlled trial.

OBJECTIVE: To compare two quality improvement (QI) interventions to improve antenatal magnesium sulphate (MgSO4 ) uptake in preterm births for the prevention of cerebral palsy. DESIGN: Unblinded cluster randomised controlled trial. SETTING: Academic Health Sciences Network, England, 2018. SAMPLE: Maternity units with ≥10 preterm deliveries annually and MgSO4 uptake of ≤70%; 40 (27 NPP, 13 enhanced support) were included (randomisation stratified by MgSO4 uptake). METHODS: The National PReCePT Programme (NPP) gave maternity units QI materials (clinical guidance, training), regional support, and midwife backfill funding. Enhanced support units received this plus extra backfill funding and unit-level QI coaching. MAIN OUTCOME MEASURES: MgSO4 uptake was compared using routine data and multivariable linear regression. Net monetary benefit was estimated, based on implementation costs, lifetime quality-adjusted life-years and societal costs. The implementation process was assessed through qualitative interviews. RESULTS: MgSO4 uptake increased in all units, with no evidence of any difference between groups (0.84 percentage points lower uptake in the enhanced group, 95% CI -5.03 to 3.35). The probability of enhanced support being cost-effective was <30%. NPP midwives gave more than their funded hours for implementation. Units varied in their support needs. Enhanced support units reported better understanding, engagement and perinatal teamwork. CONCLUSIONS: PReCePT improved MgSO4 uptake in all maternity units. Enhanced support did not further improve uptake but may improve teamwork, and more accurately represented the time needed for implementation. Targeted enhanced support, sustainability of improvements and the possible indirect benefits of stronger teamwork associated with enhanced support should be explored further.

Etiology and Ontogeny of Cerebral Palsy: Implications for Practice and Research.

Cerebral palsy (CP) has been recognized as a group of neurologic disorders with varying etiologies and ontogenies. While a percentage of CP cases arises during labor, the expanded use of electronic fetal monitoring (EFM) to include prevention of CP has resulted in decades of vastly increased interventions that have not significantly reduced the incidence of CP for infants born at term in the USA. Litigation alleging that poor obstetrical practice caused CP in most of these affected children has led to contentious arguments regarding the actual etiologies of this condition and often resulted in substantial monetary awards for plaintiffs. Recent advances in genetic testing using whole exome sequencing have revealed that at least one-third of CP cases in term infants are genetic in origin and therefore not labor-related. Here, we will present and discuss previous attempts to sort out contributing etiologies and ontogenies of CP, and how these newer diagnostic techniques are rapidly improving our ability to better detect and understand such cases. In light of these developments, we present our vision for an overarching spectrum for proper categorization of CP cases into that the following groups: (1) those begun at conception from genetic causes (nonpreventable); (2) those stemming from adverse antenatal/pre-labor events (possibly preventable with heightened antepartum assessment); (3) Those arising from intrapartum events (potentially preventable by earlier interventions); (4) Those occurring shortly after birth (possibly preventable with closer neonatal monitoring); (5) Those that appear later in the postnatal period from non-labor-related causes such as untreated infections or postnatal intracranial hemorrhages.

Cerebral Palsy - Early Diagnosis and Intervention Trial: protocol for the prospective multicentre CP-EDIT study with focus on diagnosis, prognostic factors, and intervention.

BACKGROUND: Early diagnosis of cerebral palsy (CP) is important to enable intervention at a time when neuroplasticity is at its highest. Current mean age at diagnosis is 13 months in Denmark. Recent research has documented that an early-diagnosis set-up can lower diagnostic age in high-risk infants. The aim of the current study is to lower diagnostic age of CP regardless of neonatal risk factors. Additionally, we want to investigate if an early intervention program added to standard care is superior to standard care alone. METHODS: The current multicentre study CP-EDIT (Early Diagnosis and Intervention Trial) with the GO-PLAY intervention included (Goal Oriented ParentaL supported home ActivitY program), aims at testing the feasibility of an early diagnosis set-up and the GO-PLAY early intervention. CP-EDIT is a prospective cohort study, consecutively assessing approximately 500 infants at risk of CP. We will systematically collect data at inclusion (age 3-11 months) and follow a subset of participants (n = 300) with CP or at high risk of CP until the age of two years. The GO-PLAY early intervention will be tested in 80 infants with CP or high risk of CP. Focus is on eight areas related to implementation and perspectives of the families: early cerebral magnetic resonance imaging (MRI), early genetic testing, implementation of the General Movements Assessment method, analysis of the GO-PLAY early intervention, parental perspective of early intervention and early diagnosis, early prediction of CP, and comparative analysis of the Hand Assessment for Infants, Hammersmith Infant Neurological Examination, MRI, and the General Movements method. DISCUSSION: Early screening for CP is increasingly possible and an interim diagnosis of "high risk of CP" is recommended but not currently used in clinical care in Denmark. Additionally, there is a need to accelerate identification in mild or ambiguous cases to facilitate appropriate therapy early. Most studies on early diagnosis focus on identifying CP in infants below five months corrected age. Little is known about early diagnosis in the 50% of all CP cases that are discernible later in infancy. The current study aims at improving care of patients with CP even before they have an established diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov ID 22013292 (reg. date 31/MAR/2023) for the CP-EDIT cohort and ID 22041835 (reg. date 31/MAR/2023) for the GO-PLAY trial.

Efecto neuroprotector del sulfato de magnesio en prematuros. Análisis tras instaurar su protocolo de administración antenatal en un hospital terciario / Neuroprotective effect of magnesium sulfate in premature infants: Analysis after establishing an antenatal administration protocol in a tertiary care hospital

Introducción: En 2016 se desarrolló en nuestro centro un protocolo de administración antenatal de sulfato de magnesio en gestantes con riesgo de parto pretérmino inminente como método para disminuir el riesgo de parálisis cerebral (PC). Material y métodos: Se realizó un estudio observacional y retrospectivo en un hospital de nivel IIIC con objetivo principal de comparar la incidencia de PC previa y posteriormente a la puesta en marcha de este protocolo. Con respecto a los objetivos secundarios, a destacar la incidencia de déficit cognitivo, enterocolitis necrosante y mortalidad en ambos grupos. Los pacientes incluidos fueron recién nacidos prematuros por debajo de 32 semanas de edad gestacional nacidos en los años 2011-2012 (previo a la instauración del protocolo) y 2016-2018 (posteriormente a la instauración del protocolo, cuyas madres habían recibido sulfato de magnesio como neuroprotector). Las características clínicas y epidemiológicas de ambos grupos fueron comparables entre sí. Resultados: Se recogieron datos de un total de 523 pacientes, 263 y 260 de cada grupo. Con respecto al objetivo principal, no se encontraron diferencias estadísticamente significativas. Se objetivó, en el grupo de pacientes nacidos entre 2016-2018 y con edad gestacional entre 26+0 y 27+6 semanas, cuyas madres recibieron sulfato de magnesio, una reducción estadísticamente significativa de la mortalidad y del riesgo de enterocolitis necrosante grave. Conclusiones: En nuestro trabajo, el sulfato de magnesio administrado a madres en riesgo de parto prematuro, no disminuyó el riesgo de desarrollar PC. (AU)

Introduction: In 2016, a protocol was developed in our hospital for the antenatal administration of magnesium sulfate in pregnant women at risk of imminent preterm birth as a method to reduce the risk of cerebral palsy (CP). Material and methods: We conducted a retrospective observational study in a level IIIC hospital with the primary objective of comparing the incidence of CP before and after the implementation of this protocol. Among the secondary outcomes, we ought to highlight the incidence of cognitive deficits and necrotizing enterocolitis and the mortality in both groups. The sample consisted of preterm newborns delivered before 32 weeks of gestation in 2011-2012 (prior to the implementation of the protocol) and in 2016-2018 (after the implementation of the protocol, whose mothers had received magnesium sulfate for neuroprotection). The clinical and epidemiological characteristics of both groups were comparable. Results: We collected data for a total of 523 patients, 263 and 260 in each group. As regards the primary outcome, we did not find statistically significant differences between groups. We observed a statistically significant reduction in mortality and the risk of severe necrotizing enterocolitis in the group of patients born in the 2016-2018 period and between 26+0 and 27+6 weeks of gestation, whose mothers had received magnesium sulfate. Conclusions: In our study, the administration of magnesium sulfate to mothers at risk of preterm birth did not decrease the risk of developing CP. (AU)

Serie de 22 casos de ictus isquémico arterial perinatal: factores de riesgo, manejo clínico y secuelas neurológicas / A series of 22 cases of perinatal arterial ischaemic stroke: risk factors, clinical management and neurological sequelae

Introduction. Perinatal arterial ischaemic stroke (PAIS) is almost as common as in adulthood and causes significant neurological sequelae. Aim. The aim is to describe the risk situations surrounding these neonates, the clinical manifestations, the management, the cost-effectiveness of diagnostic tests and the neurological sequelae. Patients and methods. We conducted an observational study of a cohort of patients consisting of neonates with a gestational age = 35 weeks diagnosed with PAIS in our hospital between 2010 and 2021. Results. Twenty-two cases of PAIS were included, and the incidence in our centre was 1/1,869 live newborns. The data showed that 81.8% had some intrapartum risk factor and 40.9% had a combination of several risk factors. It started with seizures (mean age 27.3 hours) in 77.3% of cases. Patients with a stroke in the left hemisphere had more sequelae (77.8%) than those with a stroke on the right-hand side (16.6%) (p = 0.041), with the exception of infantile cerebral palsy (p = 0.04), while we found no difference between hemispheres in the frequency of language impairment (p = 0.06). The mean follow-up time was 6.13 ± 3.06 years. A total of 63.6% of infants had neurological sequelae: infantile cerebral palsy (40.9%), language disorders (22.7%) and intellectual disability (9%). Moreover, 18.2% developed epilepsy (between 0.25 and 1.8 years) and antiseizure treatment was maintained after discharge in 37.5% of cases in the last years of the study. Conclusions. If a newborn infant presents seizures, it is necessary to rule out the possibility of a stroke. PAIS causes neurological sequelae in over 60% of cases. Early identification is essential to improve the neurological prognosis and avoid the prolonged use of antiseizure drugs where possible. (AU)

Introducción: El ictus cerebral isquémico arterial perinatal (IIAP) es una entidad casi tan frecuente como en la época adulta, que ocasiona secuelas neurológicas importantes.ObjetivoDescribir las situaciones de riesgo que rodean a estos neonatos, la clínica que manifiestan, el manejo, la rentabilidad de las pruebas diagnósticas y las secuelas neurológicas.Pacientes y métodosEstudio observacional de una cohorte de pacientes formada por neonatos = 35 semanas de edad gestacional diagnosticados de IIAP entre 2010 y 2021 en nuestro hospital.ResultadosSe incluyeron 22 casos de IIAP, y su incidencia en nuestro centro fue de 1/1.869 recién nacidos vivos. El 81,8% tuvo algún factor de riesgo intraparto y en el 40,9% se aglutinaron varios. Comenzó con convulsiones (edad media 27,3 horas) el 77,3% de casos. Los pacientes con ictus del hemisferio izquierdo tuvieron más secuelas (77,8%) en comparación con los derechos (16,6%) (p = 0,041), a expensas de la parálisis cerebral infantil (p = 0,04), mientras no encontramos diferencia en la frecuencia de alteraciones del lenguaje (p = 0,06) entre hemisferios. El tiempo medio de seguimiento fue de 6,13 años ± 3,06. El 63,6% de los neonatos tuvo secuelas neurológicas: parálisis cerebral infantil (40,9%), trastornos del lenguaje (22,7%) y discapacidad intelectual (9%). Desarrolló epilepsia el 18,2% (entre 0,25 y 1,8 años) y se mantuvo el tratamiento anticrisis tras el alta en el 37,5% de los casos en los últimos años del estudio.ConclusionesAnte un neonato con convulsiones hay que descartar un ictus cerebral. El IIAP ocasiona secuelas neurológicas en más del 60% de los casos. Su identificación precoz es fundamental para mejorar el pronóstico neurológico y evitar el uso prolongado de fármacos anticrisis cuando resulte posible. (AU)

A follow up on the feasibility after national implementation of magnesium sulfate for neuroprotection prior to preterm birth.

INTRODUCTION: The risk for brain injury manifested as cerebral palsy is higher in very preterm born children than in term. Prenatal administration of magnesium sulfate (MgSO4 ) has been shown to be neuroprotective and reduces the proportion of very preterm born children later diagnosed with cerebral palsy. A Swedish national clinical practice guideline was implemented in March 2020, stipulating the administration of a single intravenous dose of 6 g MgSO4 1-24 h prior to delivery before gestational age 32+0, aiming for 90% treatment coverage. The aim of this study was to evaluate the feasibility of this new clinical practice guideline in the first year of its implementation. MATERIAL AND METHODS: Data on MgSO4 treatment were collected by reviewing the medical charts of women who gave birth to live born children in gestational age 22+0-31+6 during the period of March 1, 2020 to February 28, 2021, at five Swedish university hospitals. Women with pre-eclampsia, eclampsia, or high elevated liver enzymes low platelets (HELLP) were excluded. RESULTS: A total of 388 women were eligible and 79% received treatment with MgSO4 . Of the 21% not receiving treatment, 9% did not receive treatment due to lack of knowledge about the clinical practice guideline, 9% were not possible to treat and 3% had missing data. The proportion treated increased from 72% to 87% from the first to the last 3 months. Of those treated, 81% received the drug within the stipulated timeframe (mean 8.7 h, median 3.4 h). CONCLUSIONS: There was a positive trend over time in the proportion of women receiving MgSO4 treatment, but the a priori target of 90% was not reached during the first year of implementation. Our findings indicate that this target could be reached with additional information to clinicians.

Neuroprotective effect of magnesium sulfate in premature infants. Analysis after establishing an antenatal administration protocol in a tertiary care hospital.

INTRODUCTION: In 2016, a protocol was developed in our hospital for the antenatal administration of magnesium sulfate in pregnant women at risk of imminent preterm birth as a method to reduce the risk of cerebral palsy (CP). MATERIAL AND METHODS: We conducted a retrospective observational study in a level IIIC hospital with the primary objective of comparing the incidence of CP before and after the implementation of this protocol. Among the secondary outcomes, we ought to highlight the incidence of cognitive deficits and necrotizing enterocolitis and the mortality in both groups. The sample consisted of preterm newborns delivered before 32 weeks of gestation in 2011-2012 (prior to the implementation of the protocol) and in 2016-2018 (after the implementation of the protocol, whose mothers had received magnesium sulfate for neuroprotection). The clinical and epidemiological characteristics of both groups were comparable. RESULTS: We collected data for a total of 523 patients, 263 and 260 in each group. As regards the primary outcome, we did not find statistically significant differences between groups. We observed a statistically significant reduction in mortality and the risk of severe necrotizing enterocolitis in the group of patients born in the 2016-2018 period and between 26+0 and 27+6 weeks of gestation, whose mothers had received magnesium sulfate. CONCLUSIONS: In our study, the administration of magnesium sulfate to mothers at risk of preterm birth did not decrease the risk of developing CP.

Prenatal Intravenous Magnesium at 30-34 Weeks' Gestation and Neurodevelopmental Outcomes in Offspring: The MAGENTA Randomized Clinical Trial.

Importance: Intravenous magnesium sulfate 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 sulfate at 30 to 34 weeks' gestation reduces death or cerebral palsy at 2 years. Design, Setting, and Participants: This randomized 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 sulfate (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 pediatrician) 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 Maori, 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 hospitalization. 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 cesarean 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 hemorrhage (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 sulfate 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. Trial Registration: anzctr.org.au Identifier: ACTRN12611000491965.

SuPreme Study: a protocol to study the neuroprotective potential of sulfate among very/extremely preterm infants.

INTRODUCTION: Antenatal maternal magnesium sulfate (MgSO4) administration is a proven efficacious neuroprotective treatment reducing the risk of cerebral palsy (CP) among infants born preterm. Identification of the neuroprotective component with target plasma concentrations could lead to neonatal treatment with greater efficacy and accessibility. METHODS AND ANALYSIS: This is a prospective observational cohort study, in three tertiary Australian centres. Participants are preterm infants, irrespective of antenatal MgSO4 exposure, born in 2013-2020 at 24+0 to 31+6 weeks gestation, and followed up to 2 years corrected age (CA) (to September 2023). 1595 participants are required (allowing for 17% deaths/loss to follow-up) to detect a clinically significant reduction (30% relative risk reduction) in CP when sulfate concentration at 7 days of age is 1 SD above the mean.A blood sample is collected on day 7 of age for plasma sulfate and magnesium measurement. In a subset of participants multiple blood and urine samples are collected for pharmacokinetic studies, between days 1-28, and in a further subset mother/infant blood is screened for genetic variants of sulfate transporter genes.The primary outcome is CP. Surviving infants are assessed for high risk of CP at 12-14 weeks CA according to Prechtl's Method to assess General Movements. Follow-up at 2 years CA includes assessments for CP, cognitive, language and motor development, and social/behavioural difficulties.Multivariate analyses will examine the association between day 7 plasma sulfate/magnesium concentrations with adverse neurodevelopmental outcomes. A population pharmacokinetic model for sulfate in the preterm infant will be created using non-linear mixed-effects modelling. ETHICS AND DISSEMINATION: The study has been approved by Mater Misericordiae Ltd Human Research Ethics Committee (HREC/14/MHS/188). Results will be disseminated in peer-reviewed journal publications, and provided to the funding bodies. Using consumer input, a summary will be prepared for participants and consumer groups.

Caffeine and cerebral palsy: A systematic review of randomized controlled trials and cohort studies.

OBJECTIVE: To systematically review the effects of caffeine on the development of cerebral palsy (CP). DESIGN: Systematic review. SETTING: A search of five databases was performed to identify randomized controlled trials (RCT) or cohort studies published through May 2022. Studies conducted on newborns at risk of developing CP upon receiving caffeine in the first days of life were included as well. Two independent researchers assessed the screening, data extraction, and methodological quality assessment. MAIN OUTCOME MEASURES: Percentage of children with CP. RESULTS: Four studies met our inclusion criteria. The only RCT found a decreased risk (approximately 40 %) of developing CP with 20 mg/kg caffeine citrate (OR 0.59, 95 % CI 0.39, 0.89). In addition, when comparing the period over which caffeine citrate was administered, one retrospective cohort study reported that infants who received caffeine up to the second day of life were also less likely to develop CP. Some methodological issues should be highlighted: in the RCT, the differences between the groups with respect to loss to follow-up were not explored. Similarly, intention-to-treat analyses were not performed. Most cohort studies have not adequately identified the primary confounding factors. CONCLUSIONS: Caffeine could be an important intervention in preventing CP. However, few studies have assessed the effects of caffeine on the risk of CP development. Due to methodological differences, no recommendation regarding its use can be safely made. The findings suggest a positive effect of caffeine citrate in the early stages of life with approximately 20 mg/kg of weight; however, well-designed RCTs with adequate sample size and power, randomization process, outcome measurement, and data analysis are still required.

Protecting the brain of the micropreemie.

Advances in perinatal care have seen substantial improvements in survival without disability for extremely preterm infants. Protecting the developing brain and reducing neurodevelopmental sequelae of extremely preterm birth are strategic priorities for both research and clinical care. A number of evidence-based interventions exist for neuroprotection in micropreemies, inclusive of prevention of preterm birth and multiple births with implantation of only one embryo during in vitro fertilisation, as well as antenatal care to optimize fetal wellbeing, strategies for supporting neonatal transition, and neuroprotective developmental care. Avoidance of complications that trigger ischemia and inflammation is vital for minimizing brain dysmaturation and injury, particularly of the white matter. Neurodevelopmental surveillance, early diagnosis of cerebral palsy and early intervention are essential for optimizing long-term outcomes and quality of life. Research priorities include further evaluation of putative neuroprotective agents, and investigation of common neonatal interventions in trials adequately powered to assess neurodevelopmental outcome.

Effectiveness of nutritional interventions to prevent nonprogressive congenital and perinatal brain injuries: a systematic review and meta-analysis of randomized trials.

CONTEXT: Nutritional interventions for newborns with brain injury are scarce, and there are gaps in the knowledge of their mechanisms of action in preventing the occurrence of cerebral palsy (CP) or the incidence of other developmental disabilities. OBJECTIVE: The objective of this review was to assess the effect of nutritional interventions in preventing nonprogressive congenital or perinatal brain injuries, or in improving outcomes related to neurological development. DATA SOURCES: Randomized trials on any nutritional intervention for pregnant women at risk of preterm delivery, or for children with low birth weight, preterm, or with confirmed or suspected microcephaly, CP, or fetal alcohol syndrome disorders (FASDs) were retrieved from MEDLINE, Embase, Scopus, Web of Science, LILACS, and CENTRAL databases from inception to September 17, 2020. DATA EXTRACTION: Data extraction, risk of bias (Cochrane Risk of Bias tool 2), and quality of evidence (GRADE approach) were assessed by 2 authors. DATA ANALYSIS: Pooled risk ratios (RRs) with 95% confidence intervals were calculated using a random-effects meta-analysis. Seventeen studies were included on intravenous interventions (magnesium sulfate [n = 5], amino acids [n = 4], vitamin A [n = 1], and N-acetylcysteine [n = 1]); enteral interventions (vitamin D [n = 1], prebiotic [n = 1], nutrient-enriched formula [n = 1], and speed of increasing milk feeds [n = 1]); and oral interventions (choline [n = 1] and docosahexaenoic acid, choline, and uridine monophosphate [n = 1]). All studies assessed CP, except 1 on FASDs. Eight studies were judged as having high risk of bias. Five studies (7413 babies) with high-quality evidence demonstrated decreased risk of childhood CP (RR = 0.68, 95% CI: 0.52-0.88) with magnesium sulfate. Interventions with amino acids had no effect on CP prevention or other outcomes. Except for 1 study, no other intervention decreased the risk of CP or FASDs. CONCLUSION: Although different types of nutritional interventions were found, only those with antenatal magnesium sulfate were effective in decreasing CP risk in preterm infants. Well-designed, adequately powered randomized clinical trials are required.

Prevention of perinatal depression with counseling in adolescents: a cost-effectiveness analysis.

OBJECTIVE: The US Preventive Services Task Force recently recommended that clinicians refer all pregnant and postpartum individuals at increased risk of perinatal depression to a counseling intervention. Adolescents are considered a high-risk group for perinatal depression. Therefore, we examined whether it is cost effective for all pregnant adolescents to be referred for preventive counseling. STUDY DESIGN: We developed a decision-analytic model using TreeAge Pro software to compare outcomes in pregnant adolescents who received versus did not receive counseling interventions. We used a theoretical cohort of 180,000 individuals, which is the estimated annual number of births to persons ≤ 19 years in the US. Outcomes included perinatal depression, chronic depression, maternal suicide attributed to depression, preterm delivery, neonatal death, cerebral palsy, and sudden infant death syndrome (SIDS), in addition to cost and quality-adjusted life years (QALYs). The willingness-to-pay (WTP) threshold was set to $100,000/QALY. We derived model inputs from the literature, and sensitivity analyses were used to assess robustness of the model. RESULTS: A strategy of referral to counseling interventions was cost effective in our theoretical cohort, with 8935 fewer cases of perinatal depression, 1606 fewer cases of chronic depression, 166 fewer preterm deliveries, 4 fewer neonatal deaths, 1 fewer case of cerebral palsy, 20 fewer cases of SIDS. In total, there were 21,976 additional QALYs and cost savings of $223,549,872, making it the dominant strategy (better outcomes with lower costs). We found that counseling interventions remained cost saving until the annual direct and indirect cost of chronic, severe depression was set below $30,000, at which point it became cost effective (baseline input: $182,309). CONCLUSION: We found it was cost effective to refer all pregnant adolescents for preventive counseling interventions. Clinicians should develop approaches to identify and refer pregnant adolescents for behavioral counseling to prevent perinatal depression.

Antenatal magnesium sulphate for preventing cerebral palsy: An economic evaluation of the impact of a quality improvement program.

Previous work demonstrated that implementing a quality improvement (QI) program improves the uptake of guideline-recommended antenatal magnesium sulphate, a critical intervention known to reduce cerebral palsy risk. Here we estimate potential cost savings attributable to the improved uptake. By expanding coverage from 63 to 83% of eligible women, we estimated that five children potentially would not have received a diagnosis of cerebral palsy, a potential cost saving of $AU4.8 million in lifetime healthcare costs. Our findings strengthen the case for embedding QI approaches in perinatal care to reduce the incidence of cerebral palsy.

Maternal intake of folate during pregnancy and risk of cerebral palsy in the MOBAND-CP cohort.

BACKGROUND: Folate prevents neural tube defects and may play a role in some neurodevelopmental disorders. OBJECTIVES: We investigated whether higher intakes of periconceptional or midpregnancy folate, as recommended, were associated with a reduced risk of offspring cerebral palsy (CP). METHODS: We included participants from the Nordic collaboration cohort consisting of mother-child dyads in the Danish National Birth Cohort and the Norwegian Mother, Father, and Child Cohort Study [combined as MOthers and BAbies in Norway and Denmark (MOBAND-CP)]. A total of 190,989 live-born children surviving the first year of life were included. Missing covariate data were multiply imputed. Our exposures were defined as any or no folic acid supplementation in gestational weeks (GWs) -4 to 8 (periconceptional), 9 to 12, and -4 to 12, and supplemental, dietary, and total folate during midpregnancy (GWs 22-25). CP overall and the unilateral and bilateral spastic subtypes, as well as CP with low or moderate/high gross motor function impairments, were our outcomes of interest. RESULTS: Periconceptional folic acid supplementation was not associated with CP [adjusted odds ratio (aOR), 1.02; 95% CI: 0.82-1.28]. However, supplementation in GWs 9 to 12 was associated with a reduced risk of CP (aOR, 0.74; 95% CI: 0.57-0.96), and inverse associations were indicated for both the unilateral (aOR, 0.68; 95% CI: 0.46-1.02) and bilateral (aOR, 0.70; 95% CI: 0.49-1.02) spastic subtypes, although the associations were not statistically significant. Supplemental or dietary folate in midpregnancy alone were not associated with CP. Strong inverse associations were observed with low gross motor function impairment (aOR, 0.49; 95% CI: 0.29-0.83), while for unilateral CP the aOR was 0.63 (95% CI: 0.34-1.22) for intakes of ≥500 compared to ≤199 dietary folate equivalents/day during midpregnancy. CONCLUSIONS: Our findings suggest that folate intakes in GWs 9 to 12 and midpregnancy were associated with lower risks of CP, while no association was observed for periconceptional supplementation.