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.

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.

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.

Is Late Prevention of Cerebral Palsy in Extremely Preterm Infants Plausible?

Preterm birth continues to be associated with neurodevelopmental problems including cerebral palsy. Cystic white matter injury (WMI) is still the major neuropathology underlying cerebral palsy, affecting 1-3% of preterm infants. Although rates have gradually fallen over time, the pathogenesis and evolution of cystic WMI are still poorly understood. Hypoxia-ischemia (HI) remains an important contributor, yet there is no established treatment to prevent injury. Clinically, serial ultrasound and magnetic resonance imaging studies typically show delayed development of cystic lesions 2-4 weeks after birth. This raises the important and unresolved question as to whether this represents slow evolution of injury occurring around the time of birth or repeated injury over many weeks after birth. There is increasing evidence that tertiary injury after HI can contribute to impairment of white and grey matter maturation. In the present review, we discuss preclinical evidence that severe, cystic WMI can evolve for many weeks after acute HI and is associated with microglia activity. This suggests the intriguing hypothesis that the tertiary phase of injury is not as subtle as often thought and that there may be a window of therapeutic opportunity for 1 to 2 weeks after hypoxic-ischemic injury to prevent delayed cystic lesions, and so, further reduce the risk of cerebral palsy after preterm birth.

Prenatal Tobacco Exposure and Childhood Neurodevelopment among Infants Born Prematurely.

OBJECTIVE: Nicotine is an established neuroteratogen, and prenatal tobacco exposure alters the structure of the developing nervous system. An association between prenatal tobacco exposure and impaired neurologic function is less well established. We examine the association between prenatal tobacco exposure and childhood neurodevelopment among infants born preterm. STUDY DESIGN: Secondary analysis of a multicenter randomized controlled trial assessing the benefits of magnesium sulfate for the prevention of cerebral palsy in preterm infants. Women were included if they delivered a singleton and nonanomalous infant before 37 weeks. Exposure was any self-reported prenatal tobacco use. Primary outcome was the original trial composite outcome of moderate or severe cerebral palsy at 2 years of age, or stillbirth, or infant death by 1 year of age. Secondary outcomes included components of the composite and mild cerebral palsy at 2 years, Bayley Scales of Infant Development II motor and mental scores, death before two years, and use of auditory aids or corrective lenses. Multivariable logistic regression models were performed to estimate adjusted odds ratios (aOR) with 95% confidence intervals. RESULTS: Of 1,826 women included, 503 (27.5%) used tobacco. Tobacco users were more likely to be older, unmarried, and white; have a prior preterm birth; have received no prenatal care; and to use illicit drugs or alcohol. Gestational age at delivery, betamethasone exposure, and magnesium exposure were not different between groups. There were no differences in the composite primary outcome or in rates of cerebral palsy by tobacco use. Moderate developmental delay was more common among tobacco exposed in bivariate but not adjusted analysis (20.5 vs. 15.9%, p = 0.035). In adjusted analysis, tobacco exposure was associated with increased use of corrective lenses (5.0 vs. 2.9%, aOR: 2.28, 95% confidence interval: 1.28-4.07). CONCLUSION: Prenatal tobacco exposure is not associated with neurodevelopmental impairment in infants born preterm. However, tobacco exposure may be associated with impaired vision. KEY POINTS: · Tobacco exposure is not associated with impaired neurodevelopment in this preterm population.. · Prenatal tobacco exposure is associated with increased need for corrective lenses.. · Tobacco use in pregnancy may be a risk factor for poorer visual acuity in children..

Antenatal Corticosteroids and Outcomes in Preterm Twins.

OBJECTIVE: To estimate whether improvement in outcomes from antenatal corticosteroid treatment in extremely and very preterm twins is similar to that observed in singletons, and to investigate whether antenatal corticosteroid treatment has different effects according to chorionicity or birth order. METHODS: This population-based study was based on an analysis of data collected by the Neonatal Research Network of Japan from 2003 to 2015 of neonates weighing 1,500 g or less at birth, from gestational ages of 24 0/7 to 31 6/7 weeks of gestation. After propensity score matching, univariate logistic and interaction analyses were performed to compare short-term (neonatal period) and medium-term (3 years of age) outcomes of the children of mothers who received antenatal corticosteroids with those of children of mothers who did not receive antenatal corticosteroids. We focused on differences between singletons and twins, between monochorionic and dichorionic twins and between the first and second twin. RESULTS: The study comprised 23,502 singletons and 6,546 twins. Antenatal corticosteroid treatment was associated with significant decreased short-term neurologic outcomes in both singletons and twins. However, antenatal corticosteroid treatment was associated with significantly decreased mortality (odds ratio [OR] 0.61; 95% CI 0.53-0.70), respiratory distress syndrome (OR 0.71, 95% CI 0.67-0.76), and cerebral palsy (OR 0.85, 95% CI 0.72-0.99) in singletons but not in twins (OR 0.89, 95% CI 0.68-1.17; OR 0.99, 95% CI 0.87-1.12; and OR 0.82, 95% CI 0.61-1.11, respectively). No association was found between chorionicity and the efficacy of antenatal corticosteroid treatment on outcomes. Further, no association was found between birth order and the efficacy of antenatal corticosteroid treatment on outcomes, except for periventricular leukomalacia and necrotizing enterocolitis (interaction: P=.02 and P=.04, respectively). CONCLUSION: Antenatal corticosteroid treatment in twins was associated with a beneficial effect on short-term neurologic outcomes only, without improvement in other short-term and medium-term outcomes. There was no difference related to chorionicity.

Cost-effectiveness analysis of a surveillance program to prevent hip dislocation in children with cerebral palsy.

OBJECTIVE: In this study we conducted an economic evaluation of a surveillance programme to prevent hip dislocation in children with cerebral palsy. METHOD: We developed a model that compared costs and health outcomes of children with cerebral palsy with and without a surveillance programme. Information from a number of sources was combined into a decision analytical model, primarily based on data from a comparative study with a 20-year follow-up. Effectiveness was measured using Quality-Adjusted Life Years (QALYs). The analysis took the perspective of the Spanish National Health Service. We undertook extensive sensitivity analyses including a probabilistic sensitivity analysis. RESULTS: The surveillance programme led to higher QALYs and higher health care costs, with an estimated incremental cost per QALY gained of 12,282€. The results were robust to model assumptions. The probability that the programme was cost-effective was estimated to be over 80% at the threshold of 25.000€/QALY recommended in Spain. CONCLUSION: This study indicates that surveillance programmes to prevent hip dislocation in children with cerebral palsy are likely to be cost-effective.

Rede de apoio social da família para o cuidado da criança com paralisia cerebral / Social support network of the family for the care of children with cerebral palsy / Red de apoyo social de la familia para el cuidado del niño con parálisis cerebral

Objetivo: analisar a rede de apoio social utilizada pela família para cuidar a criança com paralisia cerebral. Método: pesquisa qualitativa, descritiva, realizada com 12 mães de crianças com paralisia cerebral atendidas em unidade de pediatria do Hospital Universitário de Rio Grande. Os dados foram coletados nos meses de agosto e setembro de 2018, por meio de entrevista semiestruturada, e submetidos à análise temática. Resultados: identificou-se a rede de apoio social formada pelos familiares, amigos, vizinhos, profissionais de saúde e ancorada pela fé em Deus. As mães foram protagonistas do cuidado e algumas não receberam nenhum tipo de apoio para os cuidados dos filhos. Conclusão: a rede de apoio social contribuiu para a superação de dificuldades da família e para o cuidado da criança, sendo fonte de apoio emocional, financeiro, ajuda com o transporte, remédios e orientação dos profissionais de saúde/enfermagem.

Objective: to know the social support network used by the family to care for children with cerebral palsy. Method: this qualitative and descriptive research was conducted with twelve mothers of children with cerebral palsy assisted at a pediatric unit of a University Hospital in Rio Grande. Data were collected in August and September 2018 through semi-structured interviews and submitted to thematic analysis. Results: we identified the social support network consisting of family, friends, neighbors, health professionals, and faith in God. Mothers were protagonists of care and some received no support for childcare. Conclusion: the social support network contributed to overcome family difficulties and childcare, being a source of emotional, financial support, help with transportation, medicine, and guidance from health/nursing professionals.

Objetivo: conocer la red de apoyo social utilizada por la familia para cuidar a niños con parálisis cerebral. Método: investigación cualitativa, descriptiva, realizada con doce madres de niños con parálisis cerebral atendidas en una unidad de pediatría de un Hospital Universitario de Río Grande. Los datos se recopilaron en agosto y septiembre de 2018 a través de entrevistas semiestructuradas y se sometieron a análisis temáticos. Resultados: identificamos que la red de apoyo social estaba formada por familiares, amigos, vecinos, profesionales de la salud y fe en Dios. Las madres fueron protagonistas de la atención y algunas no recibieron apoyo para el cuidado de los niños. Conclusión: la red de apoyo social contribuyó a superar las dificultades familiares y el cuidado de los niños, siendo una fuente de apoyo emocional y financiero, ayuda con el transporte, medicamentos y orientación de profesionales de la salud/enfermeros.

Magnesium Sulfate and Novel Therapies to Promote Neuroprotection.

Cerebral palsy occurs more often in preterm than in term deliveries and is one of the major neurologic injuries seen in preterm infants. Magnesium sulfate has been found to reduce the risk of cerebral palsy in patients at risk of delivery before 32 weeks' gestational age. Multiple large clinical trials have shown this effect. The authors recommend magnesium sulfate bolus followed by continuous dosing of magnesium sulfate in those at risk of delivery before 32 weeks' gestation until delivery occurs or is no longer imminent. This article also discusses novel and emerging therapies for the prevention of cerebral palsy.

Neuroprotective strategies following perinatal hypoxia-ischemia: Taking aim at NOS.

Perinatal asphyxia is characterized by oxygen deprivation and lack of perfusion in the perinatal period, leading to hypoxic-ischemic encephalopathy and sequelae such as cerebral palsy, mental retardation, cerebral visual impairment, epilepsy and learning disabilities. On cellular level PA is associated with a decrease in oxygen and glucose leading to ATP depletion and a compromised mitochondrial function. Upon reoxygenation and reperfusion, the renewed availability of oxygen gives rise to not only restoration of cell function, but also to the activation of multiple detrimental biochemical pathways, leading to secondary energy failure and ultimately, cell death. The formation of reactive oxygen species, nitric oxide and peroxynitrite plays a central role in the development of subsequent neurological damage. In this review we give insight into the pathophysiology of perinatal asphyxia, discuss its clinical relevance and summarize current neuroprotective strategies related to therapeutic hypothermia, ischemic postconditioning and pharmacological interventions. The review will also focus on the possible neuroprotective actions and molecular mechanisms of the selective neuronal and inducible nitric oxide synthase inhibitor 2-iminobiotin that may represent a novel therapeutic agent for the treatment of hypoxic-ischemic encephalopathy, both in combination with therapeutic hypothermia in middle- and high-income countries, as well as stand-alone treatment in low-income countries.

Effect of Cord Blood Magnesium Level at Birth on Non-neurologic Neonatal Outcomes.

OBJECTIVE: We examined the effects of magnesium sulfate on non-neurologic neonatal outcomes with respect to cord blood magnesium level. STUDY DESIGN: We conducted a secondary analysis of the Maternal-Fetal Medicine Units Beneficial Effects of Antenatal Magnesium (MFMU BEAM) trial comparing the upper and lower quintiles of cord blood magnesium level. Outcomes included cerebral palsy (CP), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), and assessments of mental and motor disability. Logistic regression was used to estimate adjusted odds ratios (aORs) of each outcome, controlling for gestational age (GA), birth weight, and treatment group (TG). RESULTS: A total of 1,254 women of the 2,444 included in the BEAM trial had cord blood magnesium levels recorded. GA and birth weight were lower and TG was more common in the upper quintile cohort (p < 0.001). Neonates in the upper quintile were more likely to have severe NEC (OR, 2.41, 95% confidence interval [CI]: 1.11-5.24), ROP (OR, 1.65, 95% CI: 1.05-2.59), and BPD (OR, 1.70, 95% CI: 1.04-2.73). Adjustment for covariates demonstrated no difference in the NEC, ROP, and BPD rates, although there was a decrease in rates of mental disability index < 70 which was not seen in the unadjusted analysis (aOR, 0.49, 95% CI: 0.25-0.99). CONCLUSION: Higher cord blood magnesium levels do not appear to have adverse non-neurologic effects on the neonate and may demonstrate improvement in neurologic outcomes.

Neuroproteção fetal: uma utilização contemporânea do sulfato de magnésio / Fetal neuroprotection: a contemporary use of magnesium sulfate

Os principais usos contemporâneos do sulfato de magnésio na prática obstétrica incluem a prevenção e o tratamento de convulsões em portadoras de pré-eclâmpsia e eclâmpsia, o prolongamento da gravidez para administração antenatal de corticosteroides e a neuroproteção fetal na iminência de interrupção prematura da gestação, uma indicação mais recente. A paralisia cerebral é a causa mais comum de deficiência motora na infância e apresenta como fator de risco mais importante o nascimento pré-termo, cuja incidência tem aumentado significativamente. Como consequência, a ocorrência da paralisia cerebral também tem aumentado, a despeito da melhoria da sobrevida dos fetos pré-termos. No atual contexto de procura por estratégias que se mostrem efetivas na redução da paralisia cerebral nos recém-nascidos prematuros e que deveriam ser implementadas com o objetivo de diminuir os seus efeitos danosos nos indivíduos e suas famílias, nos serviços de saúde e na sociedade como um todo, o sulfato de magnésio tem se mostrado como o mais promissor agente neuroprotetor fetal. Desde a década de 1990, estudos resultantes das suas indicações para a prevenção das convulsões eclâmpticas ou para tocólise têm evidenciado redução nas taxas de paralisia cerebral e leucomalácia periventricular em prematuros. Diretrizes nacionais e internacionais mais recentes, baseando-se em resultados de ensaios randomizados controlados e metanálises de boa qualidade, têm avançado na recomendação sobre os regimes terapêuticos e na construção de algoritmos para utilização do sulfato de magnésio na neuroproteção fetal.(AU)

The main contemporary uses of magnesium sulfate in obstetric practice include the prevention and treatment of seizures in patients with preeclampsia and eclampsia, prolongation of pregnancy for antenatal administration of corticosteroids and fetal neuroprotection at the imminence of premature termination of pregnancy, a more recent indication. Cerebral palsy is the most common cause of motor deficits in childhood and has a significant increase in preterm birth as a major risk factor. As a result, the occurrence of cerebral palsy has also increased, despite the improvement in the survival of preterm fetuses. In the current context of search for strategies that are effective in reducing cerebral palsy in preterm newborns and that should be implemented with the aim of reducing their harmful effects on individuals and their families, health services and society as a whole, magnesium sulfate has been shown to be the most promising fetal neuroprotective agent. Since the 1990s, studies arising from its indications for prevention of eclamptic seizures or tocolysis have shown a reduction in the rates of cerebral palsy and periventricular leukomalacia in preterm infants. More recent national and international guidelines, based on results from randomized controlled trials and good quality meta-analyzes, have advanced the recommendation on therapeutic regimens and the construction of algorithms for the use of magnesium sulphate in fetal neuroprotection.(AU)

Risk of neonatal and childhood morbidity among preterm infants exposed to marijuana.

BACKGROUND: Limited data exist regarding the neonatal and neurodevelopmental outcomes of infants exposed to marijuana (MJ) in-utero, particularly among preterm infants. We hypothesized that MJ-exposed preterm infants would have worse neonatal and childhood developmental outcomes compared to MJ-unexposed infants. METHODS: Secondary analysis of multicenter randomized-controlled trial of antenatal magnesium sulfate for the prevention of cerebral palsy was conducted. Singleton nonanomalous infants delivered <35 weeks exposed to MJ in-utero were compared to MJ-unexposed. Primary neonatal outcome was death, grade 3/4 intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, and/or stage II/III necrotizing enterocolitis before discharge. Primary childhood outcome was death, moderate/severe cerebral palsy, or/and Bayley II Scales <70 at age 2. Backward-stepwise regression used to estimate odds of primary outcomes. RESULTS: 1867 infants met inclusion criteria; 135(7.2%) were MJ-exposed. There were no differences in neonatal (20% vs. 26%, p = 0.14) or childhood (26% vs. 21%, p = 0.21) outcomes in MJ-exposed infants compared to MJ-unexposed infants. In adjusted models, MJ-exposure was not associated with adverse neonatal outcomes (aOR 0.83 95% CI 0.47,1.44) or early childhood outcomes (aOR 1.47, 95% CI 0.97,2.23). CONCLUSIONS: Among infants born <35 weeks of gestation, MJ-exposure was not associated with adverse neonatal or childhood outcomes. Long-term follow-up studies are needed to assess later childhood neurodevelopmental outcomes following MJ-exposure.

Lung-protective ventilatory strategies in intubated preterm neonates with RDS.

This article provides a narrative review of lung-protective ventilatory strategies (LPVS) in intubated preterm infants with RDS. A description of strategies is followed by results on short-and long-term respiratory and neurodevelopmental outcomes. Strategies will include patient-triggered or synchronized ventilation, volume targeted ventilation, the technique of intubation, surfactant administration and rapid extubation to NCPAP (INSURE), the open lung concept, strategies of high-frequency ventilation, and permissive hypercapnia. Based on this review single recommendations on optimal LPVS cannot be made. Combinations of several strategies, individually applied, most probably minimize or avoid potential serious respiratory and cerebral complications like bronchopulmonary dysplasia and cerebral palsy.

Intervención temprana en niños con alto riesgo de desarrollar parálisis cerebral: una revisión sistemática / Early intervention in infants at high-risk of developing cerebral palsy: a systematic review

El objetivo fue determinar la evidencia existente acerca de la efectividad de intervenciones tempranas sobre el desarrollo motor de niños con alto riesgo de desarrollar una parálisis cerebral. Método: Se realizó una búsqueda literaria en bases de datos y revistas relevantes para el tema (CINAHL, The Cochrane Library, EMBASE, PEDro y PubMed). Los criterios de selección consideran a recién nacidos muy prematuros (<32 semanas de gestación) y/o con extremo bajo peso al nacer (<1.500 g), recién nacidos con encefalopatías neonatales y recién nacidos (prematuros o de término) que presentan resonancia magnética anormal y/o ultrasonido craneal anormal y/o la evaluación de movimientos generales alterada. Las calidades metodológicas de los estudios se evalúan con la escala PEDro y el nivel de evidencia con la clasificación del centro basado en la Evidencia de Oxford. Resultados: Se analizaron 9 estudios, comprendiendo 687 lactantes menores de 18 meses, quienes reflejan una gran variedad respecto al tipo y frecuencia de intervenciones y las herramientas de evaluación utilizadas. Los componentes terapéuticos asociados a efectos beneficiosos son: la participación de los padres en las intervenciones y la estimulación a la producción del movimiento por parte del bebé durante las actividades de la vida diaria. Discusión: Se evidencia que programas de intervención temprana que incluyen a cuidadores para promover el desarrollo motor y cognitivo, parecen tener más efectos beneficiosos en el largo plazo. Se requiere más investigación sobre este tema, y mejoras metodológicas para resultados más consistentes y así establecer el nivel de eficacia de los programas de intervención temprana.

The goal was to determine the evidence on the effectiveness of early interventions on motor development in children at high risk of developing cerebral palsy. Method: A literature search was conducted in databases and journals relevant to the topic (CINAHL, The Cochrane Library, EMBASE, PEDro and PubMed). Selection criteria considered very preterm infants (<32 weeks’ gestation) and/or with extremely low birth weight (<1,500 g), infants with neonatal encephalopathy and newborns (preterm or term) that have abnormal MRI and/ or abnormal cranial ultrasound and / or evaluation of altered general movements. Methodological quality of the studies was assessed with the PEDro scale and level of evidence with the classification based center for Evidence of Oxford scale. Results: 9 studies were analyzed, comprising 687 infants under 18 months, which reflect a variety regarding the type and frequency of interventions and evaluation tools used. The therapeutic benefits associated components are: the involvement of parents in interventions and stimulation to production of movement by the baby during activities of daily living. Discussion: It is evident, that early intervention programs which include caregivers to promote motor and cognitive development seem to have more beneficial effects in the long run. More research on this subject, and methodological improvements for more consistent results is required, to establish the level of effectiveness of early intervention programs.

Association of Neurodevelopmental Outcomes and Neonatal Morbidities of Extremely Premature Infants With Differential Exposure to Antenatal Steroids.

Importance: Many premature infants are born without exposure to antenatal steroids (ANS) or with incomplete courses. This study evaluates the dose-dependent effect of ANS on rates of neonatal morbidities and early childhood neurodevelopmental outcomes of extremely premature infants. Objective: To compare rates of neonatal morbidities and 18- to 22-month neurodevelopmental outcomes of extremely premature infants exposed to no ANS or partial or complete courses of ANS. Design, Setting, and Participants: In this observational cohort study, participants were extremely premature infants (birth weight range, 401-1000 g; gestational age, 22-27 weeks) who were born at participating centers of the National Institute of Child Health and Human Development Neonatal Research Network between January 2006 and December 2011. Data were analyzed between October 2013 and May 2016. Main Outcomes and Measures: Rates of death or neurodevelopmental impairment at 18 to 22 months' corrected age. Neurodevelopmental impairment was defined as the presence of any of the following: moderate to severe cerebral palsy, a cognitive score less than 85 on the Bayley Scales of Infant and Toddler Development III, blindness, or deafness. Results: There were 848 infants in the no ANS group, 1581 in the partial ANS group, and 3692 in the complete ANS group; the mean (SD) birth weights were 725 (169), 760 (173), and 753 (170) g, respectively, and the mean (SD) gestational ages were 24.5 (1.4), 24.9 (2), and 25.1 (1.1) weeks. Of 6121 eligible infants, 4284 (70.0%) survived to 18- to 22-month follow-up, and data were available for 3892 of 4284 infants (90.8%). Among the no, partial, and complete ANS groups, there were significant differences in the rates of mortality (43.1%, 29.6%, and 25.2%, respectively), severe intracranial hemorrhage among survivors (23.3%, 19.1%, and 11.7%), death or necrotizing enterocolitis (48.1%, 37.1%, and 32.5%), and death or bronchopulmonary dysplasia (74.9%, 68.9%, and 65.5%). Additionally, death or neurodevelopmental impairment occurred in 68.1%, 54.4%, and 48.1% of patients in the no, partial, and complete ANS groups, respectively. Logistic regression analysis revealed that complete (odds ratio, 0.63; 95% CI, 0.53-0.76) and partial (odds ratio, 0.77; 95% CI, 0.63-0.95) ANS courses were associated with lower rates of death or neurodevelopmental impairment compared with the no ANS group. The reduction in the rate of death or neurodevelopmental impairment associated with exposure to a complete ANS course may be mediated through a reduction in rates of severe intracranial hemorrhage and/or cystic periventricular leukomalacia in the neonatal period. Conclusions and Relevance: Antenatal steroid exposure was associated with a dose-dependent protective effect against death or neurodevelopmental impairment in extremely preterm infants. The effect was partly mediated by ANS-associated reductions in rates of severe intracranial hemorrhage and/or cystic periventricular leukomalacia. These results support prompt administration of ANS, with the goal of a complete course prior to delivery.

Early developmental intervention programmes provided post hospital discharge to prevent motor and cognitive impairment in preterm infants.

BACKGROUND: Infants born preterm are at increased risk of developing cognitive and motor impairment compared with infants born at term. Early developmental interventions have been provided in the clinical setting with the aim of improving overall functional outcomes for these infants. Long-term benefits of these programmes remain unclear. OBJECTIVES: Primary objective To compare the effectiveness of early developmental intervention programmes provided post hospital discharge to prevent motor or cognitive impairment in preterm (< 37 weeks) infants versus standard medical follow-up of preterm infants at infancy (zero to < three years), preschool age (three to < five years), school age (five to < 18 years) and adulthood (≥ 18 years). Secondary objectives To perform subgroup analyses to determine the following.• Effects of gestational age, birth weight and brain injury (periventricular leukomalacia (PVL)/intraventricular haemorrhage (IVH)) on cognitive and motor outcomes when early intervention is compared with standard follow-up. ∘ Gestational age: < 28 weeks, 28 to < 32 weeks, 32 to < 37 weeks. ∘ Birth weight: < 1000 grams, 1000 to < 1500 grams, 1500 to < 2500 grams. ∘ Brain injury: absence or presence of grade III or grade IV IVH or cystic PVL (or both) or an abnormal ultrasound/magnetic resonance image (MRI) before initiation of the intervention.• Effects of interventions started during inpatient stay with a post-discharge component versus standard follow-up care.• Effects of interventions focused on the parent-infant relationship, infant development or both compared with standard follow-up care.To perform sensitivity analysis to identify the following.• Effects on motor and cognitive impairment when early developmental interventions are provided within high-quality randomised trials with low risk of bias for sequence generation, allocation concealment, blinding of outcome measures and selective reporting bias. SEARCH METHODS: The search strategy of the Cochrane Neonatal Review Group was used to identify randomised and quasi-randomised controlled trials of early developmental interventions provided post hospital discharge. Two review authors independently searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Advanced, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and EMBASE (1966 to August 2015). SELECTION CRITERIA: Studies included had to be randomised or quasi-randomised controlled trials of early developmental intervention programmes that began within the first 12 months of life for infants born before 37 weeks' gestational age. Interventions could commence on an inpatient basis but had to include a post-discharge component for inclusion in this review. Outcome measures were not prespecified, other than that they had to assess cognitive outcomes, motor outcomes or both. Rates of cerebral palsy were documented. DATA COLLECTION AND ANALYSIS: Two independent review authors extracted and entered data. Cognitive and motor outcomes were pooled by four age groups: infancy (zero to < three years), preschool age (three to < five years), school age (five to < 18 years) and adulthood (≥ 18 years). Meta-analysis using RevMan 5.1 was carried out to determine the effects of early developmental interventions at each age range. Subgroup analyses focused on gestational age, birth weight, brain injury, commencement of the intervention, focus of the intervention and study quality. MAIN RESULTS: Twenty-five studies met the inclusion criteria (3615 randomly assigned participants). Only 12 of these studies were randomised controlled trials with appropriate allocation concealment. Variability was evident with regard to focus and intensity of the intervention, participant characteristics and length of follow-up. Meta-analysis led to the conclusion that intervention improved cognitive outcomes at infancy (developmental quotient (DQ): standardised mean difference (SMD) 0.32 standard deviations (SDs), 95% confidence interval (CI) 0.16 to 0.47; P value < 0.001; 16 studies; 2372 participants) and at preschool age (intelligence quotient (IQ); SMD 0.43 SDs, 95% CI 0.32 to 0.54; P value < 0.001; eight studies; 1436 participants). However, this effect was not sustained at school age (IQ: SMD 0.18 SDs, 95% CI -0.08 to 0.43; P value = 0.17; five studies; 1372 participants). Heterogeneity between studies for cognitive outcomes at infancy and at school age was significant. With regards to motor outcomes, meta-analysis of 12 studies showed a significant effect in favour of early developmental interventions at infancy only; however, this effect was small (motor scale DQ: SMD 0.10 SDs, 95% CI 0.01 to 0.19; P value = 0.03; 12 studies; 1895 participants). No effect was noted on the rate of cerebral palsy among survivors (risk ratio (RR) 0.82, 95% CI 0.52 to 1.27; seven studies; 985 participants). Little evidence showed a positive effect on motor outcomes in the long term, but only five included studies reported outcomes at preschool age (n = 3) or at school age (n = 2). AUTHORS' CONCLUSIONS: Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with cognitive benefits persisting into preschool age. A great deal of heterogeneity between studies was due to the variety of early developmental intervention programmes tested and to gestational ages of included preterm infants; thus, comparisons of intervention programmes were limited. Further research is needed to determine which early developmental interventions are most effective in improving cognitive and motor outcomes, and to discern the longer-term effects of these programmes.

Antenatal Magnesium and Cerebral Palsy in Preterm Infants.

OBJECTIVE: To evaluate the relationship of maternal antenatal magnesium sulfate (MgSO4) with neonatal cranial ultrasound abnormalities and cerebral palsy (CP). STUDY DESIGN: In a randomized trial of MgSO4 or placebo in women at high risk of preterm delivery, up to 3 cranial ultrasounds were obtained in the neonatal period. Images were reviewed by at least 2 pediatric radiologists masked to treatment and other clinical conditions. Diagnoses were predefined for intraventricular hemorrhage, periventricular leukomalacia, intracerebral echolucency or echodensity, and ventriculomegaly. CP was diagnosed at 2 years of age by standardized neurologic examination. RESULTS: Intraventricular hemorrhage, periventricular leukomalacia, intracerebral echolucency or echodensity, and ventriculomegaly were all strongly associated with an increased risk of CP. MgSO4 administration did not affect the risk of cranial ultrasound abnormality observed at 35 weeks postmenstrual age or later. However, for the 82% of infants born at <32 weeks gestation, MgSO4 was associated with a reduction in risk of echolucency or echodensity. The reduction in risk for echolucency explained 21% of the effect of MgSO4 on CP (P = .04), and for echodensity explained 20% of the effect (P = .02). CONCLUSIONS: MgSO4 given prior to preterm delivery was associated with decreased risk of developing echodensities and echolucencies at <32 weeks gestation. However, this effect can only partially explain the effect of MgSO4 on CP at 2 years of age. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00014989.