Magnesium Sulfate Before Preterm Birth for Neuroprotection: An Updated Cochrane Systematic Review.

OBJECTIVE: To systematically review the evidence for the effectiveness and safety of magnesium sulfate as a fetal neuroprotective agent when given to individuals at risk of preterm birth. DATA SOURCES: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (through March 17, 2023), and reference lists of relevant studies. METHODS OF STUDY SELECTION: Randomized controlled trials (RCTs) assessing magnesium sulfate for fetal neuroprotection in pregnant participants at risk of imminent preterm birth were eligible. Two authors assessed RCTs for inclusion, extracted data, and evaluated risk of bias, trustworthiness, and evidence certainty (GRADE [Grading of Recommendations Assessment, Development and Evaluation]). TABULATION, INTEGRATION, AND RESULTS: We included six RCTs (5,917 pregnant participants and 6,759 fetuses at less than 34 weeks of gestation at randomization). They were conducted in high-income countries (two in the United States, two across Australia and New Zealand, and one each in Denmark and France) and commenced between 1995 and 2018. Primary outcomes: up to 2 years of corrected age, magnesium sulfate compared with placebo reduced the risk of cerebral palsy (risk ratio [RR] 0.71, 95% CI, 0.57-0.89; six RCTs, 6,107 children) and death or cerebral palsy (RR 0.87, 95% CI, 0.77-0.98; six RCTs, 6,481 children) (high-certainty evidence). Magnesium sulfate had little or no effect on death up to 2 years of corrected age (moderate-certainty evidence) or these outcomes at school age (low-certainty evidence). Although there was little or no effect on death or cardiac or respiratory arrest for pregnant individuals (low-certainty evidence), magnesium sulfate increased adverse effects severe enough to stop treatment (RR 3.21, 95% CI, 1.88-5.48; three RCTs, 4,736 participants; moderate-certainty evidence). Secondary outcome: magnesium sulfate reduced the risk of severe neonatal intraventricular hemorrhage (moderate-certainty evidence). CONCLUSION: Magnesium sulfate for preterm fetal neuroprotection reduces cerebral palsy and death or cerebral palsy for children. Further research is required on longer-term benefits and harms for children, effect variation by participant and treatment characteristics, and the generalizability of findings to low- and middle-income countries. SYSTEMATIC REVIEW REGISTRATION: The review protocol was based on a standard Cochrane Pregnancy and Childbirth template and our previous Cochrane Systematic Review (doi: 10.1002/14651858.CD004661.pub3; published before the introduction of PROSPERO).

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.

Postoperative Respiratory Compromise following Cesarean Birth: The Impact of Obesity and Systemic Opioids.

Objective The aim of this study was to measure the effect of obesity and systemic opioids on respiratory events within the first 24 hours following cesarean. Methods Opioid-naive women undergoing cesarean between January 2016 and December 2017 were included in this retrospective cohort study. The primary outcome was the proportion of women experiencing at least one composite respiratory outcome (oxygen saturation less than 95% lasting 30+ seconds or need for respiratory support) within 24 hours of cesarean. The impact of obesity and total systemic opioid dose in 24 hours (measured in morphine milligram equivalents [MMEs]) on the composite respiratory compromise outcome were evaluated. Results Of 2,230 cesarean births, 790 women had at least one composite respiratory event. Predictors of the composite respiratory outcome included body mass index (BMI) as a continuous variable (odds ratio = 1.063 for every one unit increase in BMI [95% confidence interval (CI): 1.021-1.108], p = 0.003), and MME (odds ratio = 1.005 [95% CI: 1.002-1.008], p = 0.003), adjusting for magnesium sulfate use. The interaction between obesity and opioid dose demonstrated an odds ratio of 1.000 (95% CI: 0.999-1.000, p = 0.030). Conclusion The proportion of women experiencing respiratory events following cesarean birth increases with the degree of obesity and opioid dose. Key Points Respiratory events increase with obesity.Respiratory events increase with systemic opioid use.Odds ratio of respiratory events is 1.063/unit BMI increase.

Assessing the neuroprotective benefits for babies of antenatal magnesium sulphate: An individual participant data meta-analysis.

BACKGROUND: Babies born preterm are at an increased risk of dying in the first weeks of life, and those who survive have a higher rate of cerebral palsy (CP) compared with babies born at term. The aim of this individual participant data (IPD) meta-analysis (MA) was to assess the effects of antenatal magnesium sulphate, compared with no magnesium treatment, given to women at risk of preterm birth on important maternal and fetal outcomes, including survival free of CP, and whether effects differed by participant or treatment characteristics such as the reason the woman was at risk of preterm birth, why treatment was given, the gestational age at which magnesium sulphate treatment was received, or the dose and timing of the administration of magnesium sulphate. METHODS AND FINDINGS: Trials in which women considered at risk of preterm birth (<37 weeks' gestation) were randomised to magnesium sulphate or control treatment and where neurologic outcomes for the baby were reported were eligible for inclusion. The primary outcomes were infant death or CP and severe maternal outcome potentially related to treatment. Studies were identified based on the Cochrane Pregnancy and Childbirth search strategy using the terms [antenatal or prenatal] and [magnesium] and [preterm or premature or neuroprotection or 'cerebral palsy']. The date of the last search was 28 February 2017. IPD were sought from investigators with eligible trials. Risk of bias was assessed using criteria from the Cochrane Collaboration. For each prespecified outcome, IPD were analysed using a 1-stage approach. All 5 trials identified were included, with 5,493 women and 6,131 babies. Overall, there was no clear effect of magnesium sulphate treatment compared with no treatment on the primary infant composite outcome of death or CP (relative risk [RR] 0.94, 95% confidence interval (CI) 0.85 to 1.05, 6,131 babies, 5 trials, p = 0.07 for heterogeneity of treatment effect across trials). In the prespecified sensitivity analysis restricted to data from the 4 trials in which the intent of treatment was fetal neuroprotection, there was a significant reduction in the risk of death or CP with magnesium sulphate treatment compared with no treatment (RR 0.86, 95% CI 0.75 to 0.99, 4,448 babies, 4 trials), with no significant heterogeneity (p = 0.28). The number needed to treat (NNT) to benefit was 41 women/babies to prevent 1 baby from either dying or having CP. For the primary outcome of severe maternal outcome potentially related to magnesium sulphate treatment, no events were recorded from the 2 trials providing data. When the individual components of the composite infant outcome were assessed, no effect was seen for death overall (RR 1.03, 95% CI 0.91 to 1.17, 6,131 babies, 5 trials) or in the analysis of death using only data from trials with the intent of fetal neuroprotection (RR 0.95, 95% CI 0.80 to 1.13, 4,448 babies, 4 trials). For cerebral palsy in survivors, magnesium sulphate treatment had a strong protective effect in both the overall analysis (RR 0.68, 95% CI 0.54 to 0.87, 4,601 babies, 5 trials, NNT to benefit 46) and the neuroprotective intent analysis (RR 0.68, 95% CI 0.53 to 0.87, 3,988 babies, 4 trials, NNT to benefit 42). No statistically significant differences were seen for any of the other secondary outcomes. The treatment effect varied little by the reason the woman was at risk of preterm birth, the gestational age at which magnesium sulphate treatment was given, the total dose received, or whether maintenance therapy was used. A limitation of the study was that not all trials could provide the data required for the planned analyses so that combined with low event rates for some important clinical events, the power to find a difference was limited. CONCLUSIONS: Antenatal magnesium sulphate given prior to preterm birth for fetal neuroprotection prevents CP and reduces the combined risk of fetal/infant death or CP. Benefit is seen regardless of the reason for preterm birth, with similar effects across a range of preterm gestational ages and different treatment regimens. Widespread adoption worldwide of this relatively inexpensive, easy-to-administer treatment would lead to important global health benefits for infants born preterm.

Using prophylactic, but not tocolytic, magnesium sulfate to reduce cerebral palsy related to prematurity: what dose, and what about infant mortality?

Strategies for the prevention of cerebral palsy (CP) remain incompletely characterized. Recognizing that half of all cases are associated with preterm delivery (Australian CP Register Report, 2009), research protocols aimed at reducing its prevalence have focused on interventions in pregnancies at risk for preterm birth. Compelling data from recent clinical trials have led to an emerging consensus favoring the use of antenatal magnesium sulfate for preterm neuroprophylaxis. Unresolved, however, is the critical question regarding the "best dose". Acknowledging that any substance in high enough doses becomes toxic, the "best dose" is really the least dose that achieves efficacy, while minimizing potential toxicity among susceptible fetuses. Importantly, credible evidence from these CP prevention trials indicates that antenatal magnesium sulfate, if dosed appropriately, may also decrease infant mortality--a worthy goal in its own right. Accordingly, whether we achieve (a) reduction in CP only, (b) simultaneous reduction in CP and infant mortality, or (c) CP reduction offset by possibly increased pediatric mortality, may depend on selection of dose. In this Opinion paper, we review the findings of all major randomized trials that tested the magnesium hypothesis for prevention of CP. In addition, we discuss future research, in progress, that is hoped to refine estimates of best dose.

Contemporary usage of obstetric magnesium sulfate: indication, contraindication, and relevance of dose.

Magnesium sulfate, a biologically potent compound, given sometimes in extraordinarily high doses, is among the most commonly used pharmaceuticals in American obstetric practice. Although most clinicians are in accord regarding its value for seizure prophylaxis in the setting of preeclampsia, such unanimity is not the case regarding its role in preterm labor. Credible scientific data indicate not only a lack of efficacy, but also toxicity to susceptible fetuses when magnesium sulfate is used in the high dosages found in tocolysis. In apparent contrast, three recent clinical trials, although individually inconclusive, provide data from which a very recent meta-analysis affirms a potential role for magnesium sulfate in prophylaxis against fetal neurologic injury. Comparing outcomes from these trials, with attention to dosage, relationships are revealed that unify observations previously regarded as conflicting: Magnesium sulfate indeed may have both neuroprotective and fetal toxic effects. The better, and safer, neuroprotection seems to occur at comparatively low antenatal doses (perhaps in a range between 4 g and 10.5 g), whereas increasing dosages exceed a "therapeutic window" whereby, as with most drugs, toxic sequelae begin to accrue.

Relationships between umbilical cord arterial blood pH levels at delivery and Bayley Psychomotor Development Index scores in early childhood.

AIMS: To correlate data on umbilical cord arterial blood pH (pHa) levels obtained at delivery with subsequent Bayley Psychomotor Development (PDI) scores determined on the same cohort of children at age 18 months. METHODS: At delivery, we obtained umbilical cord bloods for pHa levels along with other biological parameters. Following the birth cohort prospectively, at age 18 months we did a comprehensive, blinded neurodevelopmental examination to determine a PDI score for each child. RESULTS: Over the broad range of umbilical cord arterial blood pH levels from 7.03 to 7.52, no statistically significant correlation (Pearson correlation coefficient, -0.016, P=0.88) was found between pHa at delivery and PDI scores at age 18 months. To study our finding in greater detail, we formed a subset of the data consisting only of lower pHa levels at delivery (defined as

Special relationships between fetal inflammatory response syndrome and bronchopulmonary dysplasia in neonates.

OBJECTIVE: To confirm previous known relationships between Fetal Inflammatory Response Syndrome (FIRS) and neonatal bronchopulmonary dysplasia (BPD) and to present information on previously unknown special relationships between inflammatory variables and BPD. STUDY DESIGN: At delivery, we obtained biological specimens including umbilical cord venous blood for plasma interleukin-6 levels, as well as placental histology and bacteriology. Among other neonatal outcomes, we collected prospective information on BPD. RESULTS: Of 141 newborns in the study, 16 had BPD; 79% of these had antecedent FIRS, 27% of those without FIRS had BPD. By multivariable regression, only very low birth weight (adjusted [adj] odds ratio [OR] 32.0, 95% Confidence Interval [CI] 5.0 to positive infinity) and FIRS (adj OR 5.7, 95% CI 1.1 to 42.3) remained significant risk factors. Escherichia coli, perhaps due to its pyogenic nature (strongly elicits inflammatory responses), may have had a special relationship with BPD. CONCLUSIONS: In our data, FIRS and neonatal BPD are highly associated. It is possible that certain pyogenic bacteria in the chorioamnion space may be implicated more often than others. CONDENSATION: Neonates having Fetal Inflammatory Response Syndrome at delivery may later develop BPD. Pyogenic bacteria, such as Escherichia coli, may be implicated more frequently.

A review of the role for magnesium sulphate in preterm labour.

During the last decade, the body of medical knowledge concerning the use of pharmacological doses of magnesium sulphate (MgSO(4)) for preterm labour has increased substantially. Several randomised controlled trials (RCTs) have provided compelling evidence that MgSO(4) is the drug of choice for maternal seizure prophylaxis in pre-eclampsia, whether preterm or term. In contrast, a recent Cochrane systematic review of the relevant contemporary literature has found no evidence basis to support the use of MgSO(4) for tocolysis in preterm labour. Furthermore, associated with high-dosage tocolytic MgSO(4), recent data indicate a possible increased risk for neonatal intraventricular haemorrhage (IVH), as well as increased total paediatric mortality. It is possible, on the other hand, that the prophylactic administration of much lower dosages of MgSO(4), in selected cases of preterm labour, may have a neuroprotective effect for a small number of infants.

Comparison of the use of amniocentesis in two countries with different policies for prenatal testing: the case of France and the United States.

OBJECTIVE: To compare maternal age- and education-specific use of amniocentesis in France and the United States. METHODS: We used two nationally representative datasets, National Perinatal Survey of 1998 in France (n = 12 816) and National Center for Health Statistics birth data for 1997 in the United States (n = 3 799 975). Analyses included binomial regression with test of interactions between country, maternal age and education. RESULTS: Amniocentesis use was more than threefold greater in France than in the United States (Risk Ratio (RR) 3.2, 95% CI, 3.1-3.4). This was true across maternal age and education groups. Differences in use of amniocentesis were greatest, however, for women with lower levels of education and older (>/=38 years) women. CONCLUSION: Our results suggest greater use and lesser disparities in maternal age- and education-specific use of amniocentesis in France as compared to that in the United States. These differences may be due to several factors, including differences in women's cultural values and preferences. They may also represent barriers to effective access to prenatal testing, particularly for women in lower socioeconomic groups, in the United States.

Antenatal risk factors associated with the development of lenticulostriate vasculopathy (LSV) in neonates.

OBJECTIVE: To determine the antenatal risk factors associated with neonatal lenticulostriate vasculopathy (LSV). STUDY DESIGN: Women in preterm labor were randomized to magnesium sulfate (MgSO4), other tocolytic, or saline control. The surviving babies underwent head ultrasounds (HUS) (weeks of life 1, 2, and 4) and periodic developmental examinations (months 4, 8, 12, and 18). RESULTS: Of 140 infants, 17.1% (24) had neonatal intraventricular hemorrhage (IVH), and 10.0% (14) had LSV (half of the latter (7 of 14) had both IVH and LSV). In a regression model in which other risk factors were controlled for, the association between antenatal exposures to tocolytic MgSO4 >or=50 g and LSV were significant (adjusted odds ratio (OR), 8.3; 95% confidence interval (CI), 1.5 to 45.0; p=0.01). CONCLUSION: Based on our data and their analyses, we infer that antenatal exposure to high-dosage, tocolytic MgSO4 may be associated with LSV.

Risk-benefit effects of tocolytic therapy.

Tocolytics are potent drugs that are used to interdict preterm labour. Although all of these agents have some side effects, if not frankly adverse effects under certain clinical situations, two of these drugs, the beta-mimetics and magnesium sulphate (MgSO(4)), have been found to have considerable potential for adverse maternal cardiovascular and respiratory effects. Furthermore, magnesium sulphate has been shown to have harmful, indeed, sometimes lethal, effects in some babies. Although less well established, NSAIDs, the most common example of which is indomethacin, also have some important adverse effects in fetuses. Within the limits of contemporary scientific knowledge, calcium channel blockers, such as nifedipine, appear to be among the more efficacious and safer drugs that are currently being used for tocolysis.

Association between lenticulostriate vasculopathy (LSV) and neonatal intraventricular hemorrhage (IVH).

OBJECTIVES: To determine whether there is an unconfounded association between neonatal intraventricular hemorrhage (IVH) and lenticulostriate vasculopathy (LSV (also known as thalamostriate or mineralizing vasculopathy)). STUDY DESIGN: During the conduct of the Magnesium and Neurologic Endpoints Trial (MagNET), a randomized controlled trial involving maternal, hence fetal, exposure to antenatal magnesium sulfate in the context of preterm labor, head ultrasounds were obtained for each of the surviving neonates. Because of our previous experience in the diagnosis of LSV, when ascertaining the presence of IVH, as called for by the research protocol of our study, the presence or absence of LSV was also determined. RESULTS: We found LSV to be relatively prevalent (10% (14 of 140) among surviving babies). More importantly, it was significantly associated with the occurrence of neonatal IVH, even when controlled for possible confounding (adjusted OR 9.8, 95% confidence interval 1.3 to 73.1; p=0.03). CONCLUSION: Given the known relationships between IVH and neonatal morbidity and mortality, the finding of a statistically significant association between neonatal IVH and LSV may suggest more substantial implications for the latter than previously believed.

Second overview of relationships between antenatal pharmacologic magnesium sulfate and neurologic outcomes in children.

In the last ten years, the body of scientific knowledge concerning the use of antenatal pharmacologic magnesium sulfate (MgSO4) has become substantially larger. Several randomized controlled trials have provided compelling evidence that MgSO4 is the drug of choice for maternal seizure prophylaxis in toxemia. In contrast, the recent Cochrane Systematic Review, as well as other studies, have shown there is no evidence basis for the use of MgSO4 for tocolysis. Furthermore, when tocolytic-strength doses of MgSO4 are employed, there is an excess risk for total pediatric mortality (Cochrane Systematic Review and our own previous work). It is conceivable, nonetheless, that low doses of MgSO4, when used as prophylaxis in some selected cases of preterm labor, may ultimately be shown to be neuroprotective for a relatively small number of children. Unfortunately, the indiscriminate use of high-dosage MgSO4 for attempted tocolysis in preterm labor is much more likely to cause harm than do good.